Sulfonamide inhibitors of aspartyl protease

ABSTRACT

The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 08/142,327, filed Sep. 7, 1993, now U.S. Pat. No. 5,585,397which is a continuation-in-part of U.S. patent application Ser. No.07/941,982, filed Sep. 8, 1992, now abandoned.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a novel class of sulfonamides which areaspartyl protease inhibitors. In one embodiment, this invention relatesto a novel class of HIV aspartyl protease inhibitors characterized byspecific structural and physicochemical features. This invention alsorelates to pharmaceutical compositions comprising these compounds. Thecompounds and pharmaceutical compositions of this invention areparticularly well suited for inhibiting HIV-1 and HIV-2 proteaseactivity and consequently, may be advantageously used as anti-viralagents against the HIV-1 and HIV-2 viruses. This invention also relatesto methods for inhibiting the activity of HIV aspartyl protease usingthe compounds of this invention and methods for screening compounds foranti-HIV activity.

BACKGROUND OF THE INVENTION

The human immunodeficiency virus ("HIV") is the causative agent foracquired immunodeficiency syndrome ("AIDS")--a disease characterized bythe destruction of the immune system, particularly of CD4⁺ T-cells, withattendant susceptibility to opportunistic infections--and its precursorAIDS-related complex ("ARC")--a syndrome characterized by symptoms suchas persistent generalized lymphadenopathy, fever and weight loss.

As in the case,of several other retroviruses, HIV encodes the productionof a protease which carries out post-translational cleavage of precursorpolypeptides in a process necessary for the formation of infectiousvirions (S. Crawford et al., "A Deletion Mutation in the 5' Part of thepol Gene of Moloney Murine Leukemia Virus Blocks Proteolytic Processingof the gag and pol Polyproteins", J. Virol., 53, p. 899 (1985)). Thesegene products include pol, which encodes the virion RNA-dependent DNApolymerase (reverse transcriptase), an endonuclease, HIV protease, andgag, which encodes the core-proteins of the virion (H. Toh et al.,"Close Structural Resemblance Between Putative Polymerase of aDrosophila Transposable Genetic Element 17.6 and pol gene product ofMoloney Murine Leukemia Virus", EMBO J., 4, p. 1267 (1985); L. H. Pearlet al., "A Structural Model for the Retroviral Proteases", Nature, pp.329-351 (1987); M. D. Power et al., "Nucleotide Sequence of SRV-1, aType D Simian Acquired Immune Deficiency Syndrome Retrovirus", Science,231, p 1567 (1986)).

A number of synthetic anti-viral agents have been designed to targetvarious stages in the replication cycle of HIV. These agents includecompounds which block viral binding to CD4⁺ T-lymphocytes (for example,soluble CD4), and compounds which interfere with viral replication byinhibiting viral reverse transcriptase (for example, didanosine andzidovudine (AZT)) and inhibit integration of viral DNA into cellular DNA(M. S. Hirsh and R. T. D'Aqulia, "Therapy for Human ImmunodeficiencyVirus Infection", N. Eng. J. Med., 328, p 1686 (1993)). However, suchagents, which are directed primarily to early stages of viralreplication, do not prevent the production of infectious virions inchronically infected cells. Furthermore, administration of some of theseagents in effective amounts has led to cell-toxicity and unwanted sideeffects, such as anemia and bone marrow suppression.

More recently, the focus of anti-viral drug design has been to createcompounds which inhibit the formation of infectious virions byinterfering with the processing of viral polyprotein precursors.Processing of these precursor proteins requires the action ofvirus-encoded proteases which are essential for replication (Kohl, N. E.et al. "Active HIV Protease is Required for Viral Infectivity" Proc.Natl. Acad. Sci. USA, 85, p. 4686 (1988)). The anti-viral potential ofHIV protease inhibition has been demonstrated using peptidal inhibitors.Such peptidal compounds, however, are typically large and complexmolecules that tend to exhibit poor bioavailability and are notgenerally consistent with oral administration. Accordingly, the needstill exists for compounds that can effectively inhibit the action ofviral proteases, for use as agents for preventing and treating chronicand acute viral infections.

SUMMARY OF THE INVENTION

The present invention provides a novel class of compounds, andpharmaceutically acceptable derivatives thereof, that are useful asinhibitors of aspartyl proteases, in particular, HIV aspartyl protease.These compounds can be used alone or in combination with othertherapeutic or prophylactic agents, such as anti-virals, antibiotics,immunomodulators or vaccines, for the treatment or prophylaxis of viralinfection.

According to a preferred embodiment, the compounds of this invention arecapable of inhibiting HIV viral replication in human CD₄ ⁺ T-cells.These compounds are useful as therapeutic and prophylactic agents totreat or prevent infection by HIV-1 and related viruses which may resultin asymptomatic infection, AIDS-related complex ("ARC"), acquiredimmunodeficiency syndrome ("AIDS"), or similar disease of the immunesystem.

It is a principal object of this invention to provide a novel class ofsulfonamides which are aspartyl protease inhibitors, and particularly,HIV aspartyl protease inhibitors. This novel class of sulfonamides isrepresented by formula I: ##STR1## wherein; A is selected from the groupconsisting of H; Ht; --R¹ --Ht; --R¹ --C₁ -C₆ alkyl, which may beoptionally substituted with one or more groups selected from the groupconsisting of hydroxy, C₁ -C₄ alkoxy, Ht, --O--Ht, --NR² --CO--N(R²)(R²)and --CO--N(R²)(R²); and --R¹ --C₂ -C₆ alkenyl, which may be optionallysubstituted with one or more groups selected from the group consistingof hydroxy, C₁ -C₄ alkoxy, Ht, --O--Ht, --NR² --CO--N(R²)(R²) and--CO--N(R²)(R²);

each R¹ is independently selected from the group consisting of --C(O)--,--S(O)₂ --, --C(O)--C(O)--, --O--C(O)--, --O--S(O)₂, --NR² --S(O)₂ --,--NR² --C(O)-- and --NR² --C(O)--C(O)--;

each Ht is independently selected from the group consisting of C₃ -C₇cycloalkyl; C₅ -C₇ cycloalkenyl; C₆ -C₁₀ aryl; and 5-7 memberedsaturated or unsaturated heterocycle, containing one or more heteroatomsselected from N, N(R²), O, S and S(O)_(n), wherein said heterocycle mayoptionally be benzofused; and wherein any member of said Ht may beoptionally substituted with one or more substituents selected from thegroup consisting of oxo, --OR², --R², --N(R²)(R²), --R² --OH, --CN,--CO₂ R², --C(O)--N(R²)(R²), --S(O)₂ --N(R²)(R²), --N(R²)--C(O)--R²,--C(O)--R², --S(O)_(n) --R², --OCF₃, --S(O)_(n) --R⁷, methylenedioxy,--N(R²)--S(O)₂ (R²), halo, --CF₃, --NO₂, R⁷ and --O--R⁷ ;

each R² is independently selected from the group consisting of H and C₁-C₃ alkyl optionally substituted with R⁷ ;

B, when present, is --N(R²)--C(R³)(R³)--C(O)--;

x is 0 or 1;

each R³ is independently selected from the group consisting of H, Ht, C₁-C₆ alkyl, C₂ -C₆ alkenyl, C₃ -C₆ cycloalkyl and C₅ -C₆ cycloalkenyl,wherein any member of said R³, except H, may be optionally substitutedwith one or more substituents selected from the group consisting of--OR², --C(O)--NH--R², --S(O)_(n) --N(R²)(R²), Ht, --CN, --SR², --CO₂R², NR² --C(O)--R² ;

each n is independently 1 or 2;

D and D' are independently selected from the group consisting of R⁷ ; C₁-C₄ alkyl, which may be optionally substituted with one or more groupsselected from C₃ -C₆ cycloalkyl, --OR², --R³, --O--R⁷ and R⁷ ; C₂ -C₄alkenyl, which may be optionally substituted with one or more groupsselected from the group consisting of C₃ -C₆ cycloalkyl, --OR², --R³,--O--R⁷ and R⁷ ; C₃ -C₆ cycloalkyl, which may be optionally substitutedwith or fused with R⁷ ; and C₅ -C₆ cycloalkenyl, which may be optionallysubstituted with or fused with R⁷ ;

each R⁷ is independently selected from the group consisting of phenyl;3-6 membered carbocyclic ring and 5-6 membered heterocyclic ringcontaining one or more heteroatoms selected from O, N, S, S(O)_(n) andN(R²), wherein said carbocyclic or heterocyclic ring may be saturated orunsaturated and optionally substituted with one or more groups selectedfrom the group consisting of oxo, --OR², --R², --N(R²)(R²),--N(R²)--C(O)--R², --R² --OH, --CN, --CO₂ R², --C(O)--N(R²)(R²), haloand --CF₃ ;

E is selected from the group consisting of Ht; O--Ht; Ht--Ht; --O--R³ ;--NR² R³ ; C₁ -C₆ alkyl, which may be optionally substituted with one ormore groups selected from the group consisting of R⁴ and Ht; C₂ -C₆alkenyl, which may be optionally substituted with one or more groupsselected from the group consisting of R⁴ and Ht; C₃ -C₆ saturatedcarbocycle, which may optionally be substituted with one or more groupsselected from the group consisting of R⁴ and Ht; and C₅ -C₆ unsaturatedcarbocycle, which may optionally be substituted with one or more groupsselected from the group consisting of R⁴ and Ht; and

each R⁴ is independently selected from the group consisting of --OR²,--C(O)--NHR², --S(O)₂ --NHR², halo, --NR² --C(O)--R² and --CN.

It is a also an object of this invention to provide pharmaceuticalcompositions comprising the sulfonamides of formula I and methods fortheir use as inhibitors of HIV aspartyl protease.

It is a further object of this invention to provide a novel class of HIVaspartyl protease inhibitor compounds characterized by the followingnovel combination of structural and physicochemical features:

(1) a first and a second hydrogen bond acceptor moiety, at least one ofwhich is more highly polarizable than a carbonyl, said moieties beingthe same or different, and being capable of hydrogen bonding with thehydrogen atoms of the flap water molecule of an HIV aspartyl proteasewhen the compound is bound thereto;

(2) substantially hydrophobic moieties which associate with the P₁ andP₁ ' binding pockets of said HIV aspartyl protease when the compound isbound thereto;

(3) a third hydrogen bonding moiety, which may be either a hydrogen bonddonor or acceptor, capable of simultaneously hydrogen bonding to Asp25and Asp25' of said HIV aspartyl protease when the compound is boundthereto;

(4) an additional occupied volume of space of at least 100 Å³ when thecompound is bound to the active site of said HIV aspartyl protease, saidspace overlapping with the volume of space that would be filled by anative substrate of said HIV aspartyl protease or a nonhyrolyzableisostere thereof;

(5) a deformation energy of binding of the compound to said HIV aspartylprotease of not greater than 10 kcal/mole; and

(6) a neutral or favorable enthalpic contribution from the sum of allelectrostatic interactions between the compound and the protease whenthe compound is bound to said HIV aspartyl protease.

It is also an object of this invention to provide pharmaceuticalcompositions comprising compounds having the above-mentioned featuresand methods for their use as inhibitors of HIV aspartyl protease.

It is a further object of this invention to provide a method foridentification, design, or prediction of HIV aspartyl proteaseinhibitors comprising the steps of:

(a) selecting a candidate compound of defined chemical structurecontaining a first and a second hydrogen bond acceptor moiety, at leastone of which is more highly polarizable than a carbonyl, said moietiesbeing the same or different; a third hydrogen bonding moiety, which maybe either a hydrogen bond donor or acceptor; and at least twosubstantially hydrophobic moieties;

(b) determining a low-energy conformation for binding of said compoundto the active site of an HIV aspartyl protease;

(c) evaluating the capability of said first and second hydrogen bondacceptor moieties to form hydrogen bonds to the flap water molecule ofsaid HIV aspartyl protease when said compound is bound thereto in saidconformation;

(d) evaluating the capability of said substantially hydrophobic moietiesto associate with the P₁ and P₁ ' binding pockets of said HIV aspartylprotease when said compound is bound thereto in said conformation;

(e) evaluating the capability of said third hydrogen bonding moiety toform hydrogen bonds to Asp25 and Asp25' of said HIV aspartyl proteasewhen said compound is bound thereto in said conformation;

(f) evaluating the overlap of the occupied volume of said compound whensaid compound is bound to said HIV aspartyl protease in saidconformation and the occupied volume of a native substrate of HIVaspartyl protease or a nonhydrolyzable isostere thereof, when saidpolypeptide is bound to said HIV aspartyl protease;

(g) evaluating the deformation energy of binding of said compound tosaid HIV aspartyl protease;

(h) evaluating the enthalpic contribution of the sum of allelectrostatic interactions between said compound and said HIV aspartylprotease when said compound is bound thereto in said conformation; and

(i) accepting or rejecting said candidate compound as an HIV proteaseinhbitor based upon the determinations and evaluations carried out insteps (b) through (h).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a stereo drawing of a low-energy conformation of Compound140, as predicted by computer-modelling.

FIG. 2 depicts a stereo drawing of the actual crystal structure ofCompound 140, as observed by X-ray crystallography.

FIG. 3 depicts a stereo drawing of the correlation between the predicted(thin line) and observed (thick line) conformation of Compound 140.

DETAILED DESCRIPTION OF THE DRAWINGS

In order that the invention herein described may be more fullyunderstood, the following detailed description is set forth. In thedescription, the following abbreviations are used:

    ______________________________________                                        Designation   Reagent or Fragment                                             ______________________________________                                        Ac            acetyl                                                          Me            methyl                                                          Et            ethyl                                                           Bzl           benzyl                                                          Trityl        triphenylmethyl                                                 Asn           D- or L-asparagine                                              Ile           D- or L-isoleucine                                              Phe           D- or L-phenylalanine                                           Val           D- or L-valine                                                  Boc           tert-butoxycarbonyl                                             Cbz           benzyloxycarbonyl (carbobenzyloxy)                              Fmoc          9-fluorenylmethoxycarbonyl                                      DCC           dicyclohexylcarbodiimide                                        DIC           diisopropylcarbodiimide                                         EDC           1-(3-dimethylaminopropyl)-3-                                                  ethylcarbodiimide hydrochloride                                 HOBt          1-hydroxybenzotriazole                                          HOSu          1-hydroxysuccinimide                                            TFA           trifluoroacetic acid                                            DIEA          diisopropylethylamine                                           DBU           1,8-diazabicyclo(5.4.0)undec-7-ene                              EtOAc         ethyl acetate                                                   ______________________________________                                    

The following terms are employed herein:

Unless expressly stated to the contrary, the terms "--SO₂ --" and"--S(O)₂ --" as used herein refer to a sulfone or sulfone derivative(i.e., both appended groups linked to the S), and not a sulfinate ester.

For the compounds of formula I, and intermediates thereof, thestereochemistry of the explicitly shown hydroxyl is defined relative toD on the adjacent carbon atom, when the molecule is drawn in an extendedzig-zag representation (such as that drawn for compounds of formula XI,XV, XXII, XXIII and XXXI). If both OH and D reside on the same side ofthe plane defined by the extended backbone of the compound, thestereochemistry of the hydroxyl will be referred to as "syn". If OH andD reside on opposite sides of that plane, the stereochemistry of thehydroxyl will be referred to as "anti".

The term "heterocyclic" refers to a stable 5-7 membered monocycle or8-11 membered bicyclic heterocycle which is either saturated orunsaturated, and which may be optionally benzofused if monocyclic. Eachheterocycle consists of carbon atoms and from one to four heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur. Asused herein, the terms "nitrogen and sulfur heteroatoms" include anyoxidized form of nitrogen and sulfur, and the quaternized form of anybasic nitrogen. The heterocyclic ring may be attached by any heteroatomof the cycle which results in the creation of a stable structure.Preferred heterocycles defined above include, for example,benzimidazolyl, imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl,isoquinolyl, indolyl, pyridyl, pyrrolyl, pyrrolinyl, pyrazolyl,pyrazinyl, quinoxolyl, piperidinyl, morpholinyl, thiamorpholinyl, furyl,thienyl, triazolyl, thiazolyl, β-carbolinyl, tetrazolyl, thiazolidinyl,benzofuanoyl, thiamorpholinyl sulfone, benzoxazolyl, oxopiperidinyl,oxopyrroldinyl, oxoazepinyl, azepinyl, isoxazolyl, tetrahydropyranyl,tetrahydrofuranyl, thiadiazoyl, benzodioxolyl, thiophenyl,tetrahydrothiophenyl and sulfolanyl.

The terms "HIV protease" and "HIV aspartyl protease" are usedinterchangeably and refer to the aspartyl protease encoded by the humanimmunodeficiency virus type 1 or 2. In a preferred embodiment of thisinvention, these terms refer to the human immunodeficiency virus type 1aspartyl protease.

The term "hydrophobic" refers to a moiety which tends not to dissolvereadily in water and is often fat-soluble. Hydrophobic moieties include,but are not limited to, hydrocarbons, such as alkanes, alkenes, alkynes,cycloalkanes, cycloalkenes, cycloalkynes and aromatic hydrocarbons, suchas aryls, certain saturated and unsaturated heterocycles and moietiesthat are substantially similar to the side chains of hydrophobic naturaland unnatural α-amino acids, including valine, leucine, isoleucine,methionine, phenylalanine, α-amino isobutyric acid, alloisoleucine,tyrosine, and tryptophan.

The term "substantially hydrophobic" refers to a hydrophobic moietywhich may optionally contain polar atoms or groups in the region of themoiety which are solvent exposed when the compound is bound in theactive site of an aspartyl protease.

The term "linker moiety" refers to a group within a compound, said groupconsisting of a backbone of 1-6 atoms selected from the group consistingof C, N, O, S and P, said backbone being substituted with, fused to orotherwise associated with a substantially hydrophobic group capable ofassociating with the P₁ or P₁ ' binding pocket of an HIV aspartylprotease when said compound is bound thereto. In alternative embodimentsof this invention, such linker moieties may optionally be substitutedwith a group or groups which occupy a volume of space overlapping withthe volume of space that would be filled by a native substrate of HIVaspartyl protease or a nonhydrolyzable isostere thereof.

The term "more highly polarizable than a carbonyl" refers to a moietyhaving a polarizability (α) greater than that of a carbonyl group of acorresponding aldehyde, ketone, ester or amide moiety.

The term "pharmaceutically effective amount" refers to an amounteffective in treating HIV infection in a patient. The term"prophylactically effective amount" refers to an amount effective inpreventing HIV infection in a patient. As used herein, the term"patient" refers to a mammal, including a human.

The term "pharmaceutically acceptable carrier or adjuvant" refers to anon-toxic carrier or adjuvant that may be administered to a patient,together with a compound of this invention, and which does not destroythe pharmacological activity thereof.

As used herein, the compounds of this invention, including the compoundsof formula I, are defined to include pharmaceutically acceptablederivatives thereof. A "pharmaceutically acceptable derivative" meansany pharmaceutically acceptable salt, ester, or salt of such ester, of acompound of this invention or any other compound which, uponadministration to a recipient, is capable of providing (directly orindirectly) a compound of this invention or an anti-virally activemetabolite or residue thereof.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycollic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic,benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.Other acids, such as oxalic, while not in themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds or the invention and theirpharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g.,sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C₁₋₄alkyl)₄ ⁺ salts.

The term "thiocarbamates" refers to compounds containing the functionalgroup N--SO₂ --O.

The compounds of this invention contain one or more asymmetric carbonatoms and thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. Each stereogenic carbon may be of the R or Sconfiguration. The explicitly shown hydroxyl is also preferred to be synto D, in the extended zig-zag conformation between the nitrogens shownin compounds of formula I.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm "stable", as used herein, refers to compounds which possessstability sufficient to allow manufacture and administration to a mammalby methods known in the art. Typically, such compounds are stable at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The compounds of the present invention may be used in the form of saltsderived from inorganic or organic acids. Included among such acid salts,for example, are the following: acetate, adipate, alginate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentaneprqpionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

This invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. The basicnitrogen can be quaternized with any agents known to those of ordinaryskill in the art including, for example, lower alkyl halides, such asmethyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkylsulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; and aralkyl halides including benzyl and phenethylbromides. Water or oil-soluble or dispersible products may be obtainedby such quaternization.

The novel sulfonamides of this invention are those of formula I:##STR2## wherein: A is selected from the group consisting of H; Ht; --R¹--Ht; --R¹ --C₁ -C₆ alkyl, which may be optionally substituted with oneor more groups selected from the group consisting of hydroxy, C₁ -C₄alkoxy, Ht, --O--Ht, --NR² --CO--N(R²)(R²) and --CO--N(R²)(R²); and --R¹--C₂ -C₆ alkenyl, which may be optionally substituted with one or moregroups selected from the group consisting of hydroxy, C₁ -C₄ alkoxy, Ht,--O--Ht, --NR² --CO--N(R²)(R²) and --CO--N(R²)(R²);

each R¹ is independently selected from the group consisting of --C(O)--,--S(O)₂ --, --C(O)--C(O)--, --O--C(O)--, --O--S(O)₂, --NR² --S(O)₂ --,--NR--C(O)-- and --NR² --C(O)--C(O)--;

each Ht is independently selected from the group consisting of C₃ -C₇cycloalkyl; C₅ -C₇ cycloalkenyl; C₆ -C₁₀ aryl; and 5-7 memberedsaturated or unsaturated heterocycle, containing one or more heteroatomsselected from N, N(R²), O, S and S(O)_(n), wherein said heterocycle mayoptionally be benzofused; and wherein any member of said Ht may beoptionally substituted with one or more substituents selected from thegroup consisting of oxo, --OR², --R², --N(R²)(R²), --R² --OH, --CN,--CO₂ R², --C(O)--N(R²)(R²), --S(O)₂ --N(R²)(R²), --N(R²)--C(O)--R²,--C(O)--R², --S(O)_(n) --R², --OCF₃, --S(O)_(n) --R⁷, methylenedioxy,--N(R²)--S(O)₂ (R²), halo, --CF₃, --NO₂, R⁷ and --O--R⁷ ;

each R² is independently selected from the group consisting of H and C₁-C₃ alkyl optionally substituted with R⁷ ;

B, when present, is --N(R²)--C(R³)(R³)--C(O)--;

x is 0 or 1;

each R³ is independently selected from the group consisting of H, Ht, C₁-C₆ alkyl, C₂ -C₆ alkenyl, C₃ -C₆ cycloalkyl and C₅ -C₆ cycloalkenyl,wherein any member of said R³, except H, may be optionally substitutedwith one or more substituents selected from the group consisting of--OR², --C(O)--NH--R², --S(O)_(n) --N(R²)(R²), Ht, --CN, --SR², --CO₂R², NR² --C(O)--R² ;

each n is independently 1 or 2;

D and D' are independently selected from the group consisting of R⁷ ; C₁-C₄ alkyl, which may be optionally substituted with one or more groupsselected from C₃ -C₆ cycloalkyl, --OR², --R³, --O--R⁷ and R⁷ ; C₂ -C₄alkenyl, which may be optionally substituted with one or more groupsselected from the group consisting of C₃ -C₆ cycloalkyl, --OR², --R³,--O--R⁷ and R⁷ ; C₃ -C₆ cycloalkyl, which may be optionally substitutedwith or fused with R⁷ ; and C₅ -C₆ cycloalkenyl, which may be optionallysubstituted with or fused with R⁷ ;

each R⁷ is independently selected from the group consisting of phenyl;3-6 membered carbocyclic ring and 5-6 membered heterocyclic ringcontaining one or more heteroatoms selected from O, N, S, S(O)_(n) andN(R²), wherein said carbocyclic or heterocyclic ring may be saturated orunsaturated and optionally substituted with one or more groups selectedfrom the group consisting of oxo, --OR², --R², --N(R²)(R²),--N(R²)--C(O)--R², --R² --OH, --CN, --CO₂ R², --C(O)--N(R²)(R²), haloand --CF₃ ;

E is selected from the group consisting of Ht; O--Ht; Ht--Ht; --O--R³ ;--NR² R³ ; C₁ -C₆ alkyl, which may be optionally substituted with one ormore groups selected from the group consisting of R⁴ and Ht; C₂ -C₆alkenyl, which may be optionally substituted with one or more groupsselected from the group consisting of R⁴ and Ht; C₃ -C₆ saturatedcarbocycle, which may optionally be substituted with one or more groupsselected from the group consisting of R⁴ and Ht; and C₅ -C₆ unsaturatedcarbocycle, which may optionally be substituted with one or more groupsselected from the group consisting of R⁴ and Ht; and

each R⁴ is independently selected from the group consisting of --OR²,--C(O)--NHR⁷, --S(O)₂ --NHR², halo, --NR² --C(O)--R² and --CN.

Except where expressly provided to the contrary, as used herein, thedefinitions of variables A, R¹ -R⁴, Ht, B, x, n, D, D', R⁷ and E are tobe taken as they are defined above for the compounds of formula I.

According to one embodiment of this invention, a subclass of compoundsare those compounds of formula I, and pharmaceutically acceptable saltsthereof, wherein:

A is selected from the group consisting of H; --R¹ --Ht; --R¹ --C₁ -C₆alkyl, which may be optionally substituted with one or more groupsselected from the group consisting of hydroxy, C₁ -C₄ alkoxy, Ht and--O--Ht; and --R¹ --C₂ -C₆ alkenyl, which may be optionally substitutedwith one or more groups selected from hydroxy, C₁ -C₄ alkoxy, Ht and--O--Ht;

each R¹ is independently selected from the group consisting of --C(O)--,--S(O)₂ --, --C(O)--C(O)--, --O--CO--, --O--S(O)₂ -- and --NR² --S(O)₂--;

each Ht is independently selected from the group consisting of C₃ -C₇cycloalkyl; C₅ -C₇ cycloalkehyl; C₆ -C₁₀ aryl; and 5-7 memberedsaturated or unsaturated heterocycle, containing one or more heteroatomsselected from N, O and S, which may optionally be benzofused; whereinany member of said Ht may be optionally substituted with one or moresubstituents selected from the group consisting of oxo, --OR², --R²,--N(R²)₂, --R² --OH, --CN, --CO₂ R², --C(O)--N(R²)₂ and --S(O)₂ --N(R²)₂;

each R² is independently selected from the group consisting of H and C₁-C₃ alkyl;

B, when present, is --NH--CH(R³)--C(O)--;

x is 0 or 1;

R³ is selected from the group consisting of Ht, C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₃ -C₆ cycloalkyl and C₅ -C₆ cycloalkenyl, wherein any memberof said R³ may be optionally substituted with one or more substituentsselected from the group consisting of --OR², --C(O)--NH--R², --S(O)_(n)--N(R²)₂, Ht and --CN;

n is 1 or 2;

D and D' are independently selected from the group consisting of R⁷ ; C₁-C₄ alkyl, which may be optionally substituted with C₃ -C₆ cycloalkyl orR⁷ ; C₂ -C₄ alkenyl, which may be optionally substituted with C₃ -C₆cycloalkyl or R⁷ ; C₃ -C₆ cycloalkyl, which may be optionallysubstituted or fused with R⁷ ; and C₅ -C₆ cycloalkenyl, which may beoptionally substituted or fused with R⁷ ; with the proviso that when Dis attached to N, D may not be methyl or C₂ alkenyl;

R⁷ is selected from the group consisting of phenyl; 3-6 memberedcarbocyclic ring and 5-6 membered heterocyclic ring containing one ormore heteroatoms selected from O, N and S, wherein said carbocyclic orheterocyclic ring may be saturated or unsaturated and optionallysubstituted with one or more groups selected from the group consistingof oxo, --OR², --R², --N(R²)₂, --N(R²)--C(O)R², --R² --OH, --CN, --CO₂R², --C(O)--N(R²)₂, halo and --CF₃ ;

E is selected from the group consisting of Ht; --O--R³ ; --NR² R⁵ ; C₁-C₆ alkyl, which may be optionally substituted with one or more R⁴ orHt; C₂ -C₆ alkenyl, which may be optionally substituted with one or moreR⁴ or Ht; C₃ -C₆ saturated carbocycle, which may optionally besubstituted with one or more R⁴ or Ht; and C₅ -C₆ unsaturatedcarbocycle, which may optionally be substituted with one or more R⁴ orHt;

each R⁴ is independently selected from the group consisting of --OR²,--C(O)--NHR², --S(O)₂ --NHR², halo and --CN; and

each R⁵ is independently selected from the group consisting of H and R³,with the proviso that at least one R⁵ is not H.

A preferred subclass of compounds of this invention are those compoundsof formula I having a molecular weight of less than about 700 g/mole.More preferably, the subclass of compounds of formula I have a molecularweight of less than about 600 g/mole.

Other preferred subclasses of this invention are those compounds offormulas XXII, XXIII and XXXI: ##STR3## wherein A, R³, Ht, D, D', x andE are as defined above for compounds of formula I. For ease ofreference, the two R³ moieties present in formula XXXI have been labeledR³ and R^(3').

For compounds of formula XXII, most preferred compounds are thosewherein A is R¹ --Ht and D' is C₁ -C₃ alkyl or C₃ alkenyl, wherein saidalkyl or alkenyl may optionally be substituted with one or more groupsselected from the group consisting of C₃ -C₆ cycloalkyl, --OR², --O--R⁷and R⁷ (with all other variables being defined as above for compounds offormula I). For compounds of formula XXIII, most preferred compounds arethose wherein R³ is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₅ -C₆ cycloalkyl, C₅-C₆ cycloalkenyl or a 5-6 membered saturated or unsaturated heterocycle,wherein any member of said R³ may be optionally substituted with one ormore substituents selected from the group consisting of --OR²,--C(O)--NH--R², --S(O)_(n) N(R²)(R²), Ht, --CN, --SR², --C(O)₂ R² andNR² --C(O)--R² and D' is C₁ -C₃ alkyl or C₃ alkenyl, wherein said alkylor alkenyl may optionally be substituted with one or more groupsselected from the group consisting of C₃ -C₆ cycloalkyl, --OR², --O--R⁷and R⁷ (with all other variables being defined as above for compounds offormula I).

For compounds of formula XXXI, most preferred compounds are thosewherein A is R¹ --Ht, each R³ is independently C₁ -C₆ alkyl which may beoptionally substituted with a substituent selected from the groupconsisting of --OR², --C(O)--NH--R², --S(O)_(n) N(R²)(R²), Ht, --CN,--SR², --CO₂ R² and --NR² --C(O)--R² ; D' is C₁ -C₄ alkyl, which may beoptionally substituted with a group selected from the group consistingof C₃ -C₆ cycloalkyl, --OR², --O--R⁷ ; and E is Ht, Ht--Ht and --NR² R³.

Sulfonamides of this invention include the following specific compoundscontained in Tables I-VI. In Tables I-IV and VI, A is attached throughthe right-most bond, unless otherwise expressly noted. All othersubstituents in Tables I-VI are attached via the left-most bond, unlessotherwise expressly noted.

                                      TABLE I                                     __________________________________________________________________________     ##STR4##                                                                     COMPOUND                                                                             A               R.sup.3 D'        E                                    __________________________________________________________________________            ##STR5##                                                                                      ##STR6##                                                                              ##STR7##                                                                                ##STR8##                            2                                                                                     ##STR9##                                                                                      ##STR10##                                                                             ##STR11##                                                                               ##STR12##                           3                                                                                     ##STR13##                                                                                     ##STR14##                                                                             ##STR15##                                                                               ##STR16##                           4                                                                                     ##STR17##                                                                                     ##STR18##                                                                             ##STR19##                                                                               ##STR20##                           5                                                                                     ##STR21##                                                                                     ##STR22##                                                                             ##STR23##                                                                               ##STR24##                           6                                                                                     ##STR25##                                                                                     ##STR26##                                                                             ##STR27##                                                                               ##STR28##                           7                                                                                     ##STR29##                                                                                     ##STR30##                                                                             ##STR31##                                                                               ##STR32##                           8                                                                                     ##STR33##                                                                                     ##STR34##                                                                             ##STR35##                                                                              CH.sub.3                             9                                                                                     ##STR36##                                                                                     ##STR37##                                                                             ##STR38##                                                                               ##STR39##                           10                                                                                    ##STR40##                                                                                     ##STR41##                                                                             ##STR42##                                                                               ##STR43##                           11                                                                                    ##STR44##                                                                                     ##STR45##                                                                             ##STR46##                                                                               ##STR47##                           12                                                                                    ##STR48##                                                                                     ##STR49##                                                                             ##STR50##                                                                               ##STR51##                           13                                                                                    ##STR52##                                                                                     ##STR53##                                                                             ##STR54##                                                                               ##STR55##                           14                                                                                    ##STR56##                                                                                     ##STR57##                                                                             ##STR58##                                                                               ##STR59##                           15                                                                                    ##STR60##                                                                                     ##STR61##                                                                             ##STR62##                                                                               ##STR63##                           16                                                                                    ##STR64##                                                                                     ##STR65##                                                                             ##STR66##                                                                               ##STR67##                           17                                                                                    ##STR68##                                                                                     ##STR69##                                                                             ##STR70##                                                                               ##STR71##                           18                                                                                    ##STR72##                                                                                     ##STR73##                                                                             ##STR74##                                                                               ##STR75##                           19                                                                                    ##STR76##                                                                                     ##STR77##                                                                             ##STR78##                                                                               ##STR79##                           20                                                                                    ##STR80##                                                                                     ##STR81##                                                                             ##STR82##                                                                               ##STR83##                           21                                                                                    ##STR84##                                                                                     ##STR85##                                                                             ##STR86##                                                                               ##STR87##                           22                                                                                    ##STR88##                                                                                     ##STR89##                                                                             ##STR90##                                                                               ##STR91##                           23                                                                                    ##STR92##                                                                                     ##STR93##                                                                             ##STR94##                                                                               ##STR95##                           24                                                                                    ##STR96##                                                                                     ##STR97##                                                                             ##STR98##                                                                               ##STR99##                           25                                                                                    ##STR100##                                                                                    ##STR101##                                                                            ##STR102##                                                                              ##STR103##                          26                                                                                    ##STR104##                                                                                    ##STR105##                                                                            ##STR106##                                                                              ##STR107##                          __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________     ##STR108##                                                                   COMPOUND                                                                             A                  D'             E                                    __________________________________________________________________________    27                                                                                    ##STR109##                                                                                       ##STR110##                                                                                   ##STR111##                          28                                                                                    ##STR112##                                                                                       ##STR113##                                                                                   ##STR114##                          29                                                                                    ##STR115##                                                                                       ##STR116##                                                                                   ##STR117##                          30                                                                                    ##STR118##                                                                                       ##STR119##                                                                                   ##STR120##                          31                                                                                    ##STR121##                                                                                       ##STR122##                                                                                   ##STR123##                          32                                                                                    ##STR124##                                                                                       ##STR125##                                                                                   ##STR126##                          33                                                                                    ##STR127##                                                                                       ##STR128##                                                                                   ##STR129##                          34                                                                                    ##STR130##                                                                                       ##STR131##                                                                                   ##STR132##                          35                                                                                    ##STR133##                                                                                       ##STR134##                                                                                   ##STR135##                          36                                                                                    ##STR136##                                                                                       ##STR137##                                                                                   ##STR138##                          37                                                                                    ##STR139##                                                                                       ##STR140##                                                                                   ##STR141##                          38                                                                                    ##STR142##                                                                                       ##STR143##                                                                                   ##STR144##                          39                                                                                    ##STR145##                                                                                       ##STR146##                                                                                   ##STR147##                          40                                                                                    ##STR148##                                                                                       ##STR149##                                                                                   ##STR150##                          41                                                                                    ##STR151##                                                                                       ##STR152##                                                                                   ##STR153##                          42                                                                                    ##STR154##                                                                                       ##STR155##                                                                                   ##STR156##                          43                                                                                    ##STR157##                                                                                       ##STR158##                                                                                   ##STR159##                          44                                                                                    ##STR160##                                                                                       ##STR161##                                                                                   ##STR162##                          45                                                                                    ##STR163##                                                                                       ##STR164##                                                                                   ##STR165##                          46                                                                                    ##STR166##                                                                                       ##STR167##                                                                                   ##STR168##                          47                                                                                    ##STR169##                                                                                       ##STR170##                                                                                   ##STR171##                          48                                                                                    ##STR172##                                                                                       ##STR173##                                                                                   ##STR174##                          49                                                                                    ##STR175##                                                                                       ##STR176##                                                                                   ##STR177##                          50                                                                                    ##STR178##                                                                                       ##STR179##                                                                                   ##STR180##                          51                                                                                    ##STR181##                                                                                       ##STR182##                                                                                   ##STR183##                          52                                                                                    ##STR184##                                                                                       ##STR185##                                                                                   ##STR186##                          53                                                                                    ##STR187##                                                                                       ##STR188##                                                                                   ##STR189##                          54                                                                                    ##STR190##                                                                                       ##STR191##                                                                                   ##STR192##                          55                                                                                    ##STR193##                                                                                       ##STR194##                                                                                   ##STR195##                          56                                                                                    ##STR196##                                                                                       ##STR197##                                                                                   ##STR198##                          57                                                                                    ##STR199##                                                                                       ##STR200##                                                                                   ##STR201##                          58                                                                                    ##STR202##                                                                                       ##STR203##                                                                                   ##STR204##                          59                                                                                    ##STR205##                                                                                       ##STR206##                                                                                   ##STR207##                          60                                                                                    ##STR208##                                                                                       ##STR209##                                                                                   ##STR210##                          61                                                                                    ##STR211##                                                                                       ##STR212##                                                                                   ##STR213##                          62                                                                                    ##STR214##                                                                                       ##STR215##                                                                                   ##STR216##                          63                                                                                    ##STR217##                                                                                       ##STR218##                                                                                   ##STR219##                          64                                                                                    ##STR220##                                                                                       ##STR221##                                                                                   ##STR222##                          65                                                                                    ##STR223##                                                                                       ##STR224##                                                                                   ##STR225##                          66                                                                                    ##STR226##                                                                                       ##STR227##                                                                                   ##STR228##                          67                                                                                    ##STR229##                                                                                       ##STR230##                                                                                   ##STR231##                          68                                                                                    ##STR232##                                                                                       ##STR233##                                                                                   ##STR234##                          69                                                                                    ##STR235##                                                                                       ##STR236##                                                                                   ##STR237##                          70                                                                                    ##STR238##                                                                                       ##STR239##                                                                                   ##STR240##                          71                                                                                    ##STR241##                                                                                       ##STR242##                                                                                   ##STR243##                          72                                                                                    ##STR244##                                                                                       ##STR245##                                                                                   ##STR246##                          73                                                                                    ##STR247##                                                                                       ##STR248##                                                                                   ##STR249##                          74                                                                                    ##STR250##                                                                                       ##STR251##                                                                                   ##STR252##                          75                                                                                    ##STR253##                                                                                       ##STR254##                                                                                   ##STR255##                          76                                                                                    ##STR256##                                                                                       ##STR257##                                                                                   ##STR258##                          77                                                                                    ##STR259##                                                                                       ##STR260##                                                                                   ##STR261##                          78                                                                                    ##STR262##                                                                                       ##STR263##                                                                                   ##STR264##                          79                                                                                    ##STR265##                                                                                       ##STR266##                                                                                   ##STR267##                          80                                                                                    ##STR268##                                                                                       ##STR269##                                                                                   ##STR270##                          81                                                                                    ##STR271##                                                                                       ##STR272##                                                                                   ##STR273##                          82                                                                                    ##STR274##                                                                                       ##STR275##                                                                                   ##STR276##                          83                                                                                    ##STR277##                                                                                       ##STR278##                                                                                   ##STR279##                          84                                                                                    ##STR280##                                                                                       ##STR281##                                                                                   ##STR282##                          86                                                                                    ##STR283##                                                                                       ##STR284##                                                                                   ##STR285##                          86                                                                                    ##STR286##                                                                                       ##STR287##                                                                                   ##STR288##                          87                                                                                    ##STR289##                                                                                       ##STR290##                                                                                   ##STR291##                          88                                                                                    ##STR292##                                                                                       ##STR293##                                                                                   ##STR294##                          89                                                                                    ##STR295##                                                                                       ##STR296##                                                                                   ##STR297##                          90                                                                                    ##STR298##                                                                                       ##STR299##                                                                                   ##STR300##                          91                                                                                    ##STR301##                                                                                       ##STR302##                                                                                   ##STR303##                          92                                                                                    ##STR304##                                                                                       ##STR305##                                                                                   ##STR306##                          93                                                                                    ##STR307##                                                                                       ##STR308##                                                                                   ##STR309##                          94                                                                                    ##STR310##                                                                                       ##STR311##                                                                                   ##STR312##                          95                                                                                    ##STR313##                                                                                       ##STR314##                                                                                   ##STR315##                          96                                                                                    ##STR316##                                                                                       ##STR317##                                                                                   ##STR318##                          97                                                                                    ##STR319##                                                                                       ##STR320##                                                                                   ##STR321##                          98                                                                                    ##STR322##                                                                                       ##STR323##                                                                                   ##STR324##                          99                                                                                    ##STR325##                                                                                       ##STR326##                                                                                   ##STR327##                          100                                                                                   ##STR328##                                                                                       ##STR329##                                                                                   ##STR330##                          101                                                                                   ##STR331##        CH.sub.3                                                                                      ##STR332##                          102                                                                                   ##STR333##                                                                                       ##STR334##                                                                                   ##STR335##                          103                                                                                   ##STR336##                                                                                       ##STR337##                                                                                   ##STR338##                          104                                                                                   ##STR339##                                                                                       ##STR340##                                                                                   ##STR341##                          105                                                                                   ##STR342##                                                                                       ##STR343##                                                                                   ##STR344##                          106                                                                                   ##STR345##                                                                                       ##STR346##                                                                                   ##STR347##                          107                                                                                   ##STR348##                                                                                       ##STR349##                                                                                   ##STR350##                          108                                                                                   ##STR351##                                                                                       ##STR352##                                                                                   ##STR353##                          109                                                                                   ##STR354##                                                                                       ##STR355##                                                                                   ##STR356##                          110                                                                                   ##STR357##                                                                                       ##STR358##                                                                                   ##STR359##                          111                                                                                   ##STR360##                                                                                       ##STR361##                                                                                   ##STR362##                          112                                                                                   ##STR363##                                                                                       ##STR364##                                                                                   ##STR365##                          113                                                                                   ##STR366##                                                                                       ##STR367##                                                                                   ##STR368##                          114                                                                                   ##STR369##                                                                                       ##STR370##                                                                                   ##STR371##                          115                                                                                   ##STR372##                                                                                       ##STR373##                                                                                   ##STR374##                          116                                                                                   ##STR375##                                                                                       ##STR376##                                                                                   ##STR377##                          117                                                                                   ##STR378##                                                                                       ##STR379##                                                                                   ##STR380##                          118                                                                                   ##STR381##                                                                                       ##STR382##                                                                                   ##STR383##                          119                                                                                   ##STR384##                                                                                       ##STR385##                                                                                   ##STR386##                          120                                                                                   ##STR387##                                                                                       ##STR388##                                                                                   ##STR389##                          121                                                                                   ##STR390##                                                                                       ##STR391##                                                                                   ##STR392##                          112                                                                                   ##STR393##                                                                                       ##STR394##                                                                                   ##STR395##                          123                                                                                   ##STR396##                                                                                       ##STR397##                                                                                   ##STR398##                          124                                                                                   ##STR399##                                                                                       ##STR400##                                                                                   ##STR401##                          125                                                                                   ##STR402##                                                                                       ##STR403##                                                                                   ##STR404##                          126                                                                                   ##STR405##        CH.sub.3                                                                                      ##STR406##                          127                                                                                   ##STR407##        CH.sub.3                                                                                      ##STR408##                          128                                                                                   ##STR409##        CH.sub.3                                                                                      ##STR410##                          129                                                                                   ##STR411##                                                                                       ##STR412##                                                                                   ##STR413##                          130                                                                                   ##STR414##                                                                                       ##STR415##                                                                                   ##STR416##                          131                                                                                   ##STR417##                                                                                       ##STR418##                                                                                   ##STR419##                          132                                                                                   ##STR420##                                                                                       ##STR421##                                                                                   ##STR422##                          133                                                                                   ##STR423##                                                                                       ##STR424##                                                                                   ##STR425##                          134                                                                                   ##STR426##                                                                                       ##STR427##                                                                                   ##STR428##                          135                                                                                   ##STR429##                                                                                       ##STR430##                                                                                   ##STR431##                          136                                                                                   ##STR432##                                                                                       ##STR433##                                                                                   ##STR434##                          137                                                                                   ##STR435##                                                                                       ##STR436##                                                                                   ##STR437##                          138                                                                                   ##STR438##                                                                                       ##STR439##                                                                                   ##STR440##                          139                                                                                   ##STR441##                                                                                       ##STR442##                                                                                   ##STR443##                          140                                                                                   ##STR444##                                                                                       ##STR445##                                                                                   ##STR446##                          141                                                                                   ##STR447##                                                                                       ##STR448##                                                                                   ##STR449##                          142                                                                                   ##STR450##                                                                                       ##STR451##                                                                                   ##STR452##                          143                                                                                   ##STR453##                                                                                       ##STR454##                                                                                   ##STR455##                          144                                                                                   ##STR456##                                                                                       ##STR457##                                                                                   ##STR458##                          145                                                                                   ##STR459##                                                                                       ##STR460##                                                                                   ##STR461##                          146                                                                                   ##STR462##                                                                                       ##STR463##                                                                                   ##STR464##                          147                                                                                   ##STR465##                                                                                       ##STR466##                                                                                   ##STR467##                          148                                                                                   ##STR468##                                                                                       ##STR469##                                                                                   ##STR470##                          149                                                                                   ##STR471##                                                                                       ##STR472##                                                                                   ##STR473##                          150                                                                                   ##STR474##                                                                                       ##STR475##                                                                                   ##STR476##                          151                                                                                   ##STR477##                                                                                       ##STR478##                                                                                   ##STR479##                          152                                                                                   ##STR480##                                                                                       ##STR481##                                                                                   ##STR482##                          153                                                                                   ##STR483##                                                                                       ##STR484##                                                                                   ##STR485##                          154                                                                                   ##STR486##                                                                                       ##STR487##                                                                                   ##STR488##                          155                                                                                   ##STR489##                                                                                       ##STR490##                                                                                   ##STR491##                          156                                                                                   ##STR492##                                                                                       ##STR493##                                                                                   ##STR494##                          157                                                                                   ##STR495##                                                                                       ##STR496##                                                                                   ##STR497##                          158                                                                                   ##STR498##                                                                                       ##STR499##                                                                                   ##STR500##                          159                                                                                   ##STR501##                                                                                       ##STR502##                                                                                   ##STR503##                          160                                                                                   ##STR504##                                                                                       ##STR505##                                                                                   ##STR506##                          161                                                                                   ##STR507##                                                                                       ##STR508##                                                                                   ##STR509##                          162                                                                                   ##STR510##                                                                                       ##STR511##                                                                                   ##STR512##                          163                                                                                   ##STR513##                                                                                       ##STR514##                                                                                   ##STR515##                          164                                                                                   ##STR516##                                                                                       ##STR517##                                                                                   ##STR518##                          165                                                                                   ##STR519##                                                                                       ##STR520##                                                                                   ##STR521##                          166                                                                                   ##STR522##                                                                                       ##STR523##                                                                                   ##STR524##                          167                                                                                   ##STR525##                                                                                       ##STR526##                                                                                   ##STR527##                          168                                                                                   ##STR528##                                                                                       ##STR529##                                                                                   ##STR530##                          169                                                                                   ##STR531##                                                                                       ##STR532##                                                                                   ##STR533##                          170                                                                                   ##STR534##                                                                                       ##STR535##                                                                                   ##STR536##                          171                                                                                   ##STR537##                                                                                       ##STR538##                                                                                   ##STR539##                          172                                                                                   ##STR540##                                                                                       ##STR541##                                                                                   ##STR542##                          173                                                                                   ##STR543##                                                                                       ##STR544##                                                                                   ##STR545##                          174                                                                                   ##STR546##                                                                                       ##STR547##                                                                                   ##STR548##                          175                                                                                   ##STR549##                                                                                       ##STR550##                                                                                   ##STR551##                          176                                                                                   ##STR552##                                                                                       ##STR553##                                                                                   ##STR554##                          177                                                                                   ##STR555##                                                                                       ##STR556##                                                                                   ##STR557##                          178                                                                                   ##STR558##                                                                                       ##STR559##                                                                                   ##STR560##                          179                                                                                   ##STR561##                                                                                       ##STR562##                                                                                   ##STR563##                          180                                                                                   ##STR564##                                                                                       ##STR565##                                                                                   ##STR566##                          181                                                                                   ##STR567##                                                                                       ##STR568##                                                                                   ##STR569##                          182                                                                                   ##STR570##                                                                                       ##STR571##                                                                                   ##STR572##                          183                                                                                   ##STR573##                                                                                       ##STR574##                                                                                   ##STR575##                          184                                                                                   ##STR576##                                                                                       ##STR577##                                                                                   ##STR578##                          185                                                                                   ##STR579##                                                                                       ##STR580##                                                                                   ##STR581##                          1001                                                                                  ##STR582##                                                                                       ##STR583##                                                                                   ##STR584##                          1002                                                                                  ##STR585##                                                                                       ##STR586##                                                                                   ##STR587##                          1003                                                                                  ##STR588##                                                                                       ##STR589##                                                                                   ##STR590##                          1004                                                                                  ##STR591##                                                                                       ##STR592##                                                                                   ##STR593##                          1005                                                                                  ##STR594##        CH.sub.3                                                                                      ##STR595##                          1006                                                                                  ##STR596##                                                                                       ##STR597##                                                                                   ##STR598##                          1007                                                                                  ##STR599##                                                                                       ##STR600##                                                                                   ##STR601##                          1008                                                                                  ##STR602##                                                                                       ##STR603##                                                                                   ##STR604##                          1009                                                                                  ##STR605##                                                                                       ##STR606##                                                                                   ##STR607##                          1010                                                                                  ##STR608##                                                                                       ##STR609##                                                                                   ##STR610##                          1011                                                                                  ##STR611##                                                                                       ##STR612##                                                                                   ##STR613##                          1012                                                                                  ##STR614##                                                                                       ##STR615##                                                                                   ##STR616##                          1013                                                                                  ##STR617##                                                                                       ##STR618##                                                                                   ##STR619##                          1014                                                                                  ##STR620##                                                                                       ##STR621##                                                                                   ##STR622##                          1015                                                                                  ##STR623##                                                                                       ##STR624##                                                                                   ##STR625##                      

    TABLE III                                                                     __________________________________________________________________________     ##STR626##                                                                   COMPOUND                                                                             A                D'        E                                           __________________________________________________________________________    186                                                                                   ##STR627##                                                                                     ##STR628##                                                                              ##STR629##                                 187                                                                                   ##STR630##                                                                                     ##STR631##                                                                              ##STR632##                                 188                                                                                   ##STR633##                                                                                     ##STR634##                                                                              ##STR635##                                 __________________________________________________________________________

                  TABLE IV                                                        ______________________________________                                         ##STR636##                                                                   COMPOUND    A                                                                 ______________________________________                                        189                                                                                        ##STR637##                                                       190                                                                                        ##STR638##                                                       ______________________________________                                    

                  TABLE V                                                         ______________________________________                                         ##STR639##                                                                   COMPOUND E                                                                    ______________________________________                                        191                                                                                     ##STR640##                                                          192                                                                                     ##STR641##                                                          193                                                                                     ##STR642##                                                          194                                                                                     ##STR643##                                                          ______________________________________                                    

                  TABLE VI                                                        ______________________________________                                         ##STR644##                                                                   COMPOUND    D             D'                                                  ______________________________________                                        195                                                                                        ##STR645##                                                                                  ##STR646##                                         196                                                                                        ##STR647##                                                                                  ##STR648##                                         ______________________________________                                    

Preferred compounds of this invention are*:

(S)-N-1-(3-((3-Acetylamino-4-fluorobenzenesulfonyl)-benzyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamideand(S)-N-1-(3-((4-Acetylamino-3-fluorobenzenesulfonyl)-benzyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compounds 2);

(S)-N-1-(3-((5-Acetylamino-3-methyl-thiophene-2-sulfonyl)-benzyl-amino)-(1S,2syn)-1-benzyl-2-hydroxypropyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 5);

(S)-N-1-(1-Benzyl-3-(benzyl-(5-isoxazol-3-yl-thiophene-2-sulfonyl)-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 6);

(S)-N-1-(3-((Benzo(1,2,5)oxadiazole-4-sulfonyl)-benzyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 9);

N-1-(1-(S)-Benzyl-3-(benzyl-(3-sulfamoyl-benzenesulfonyl)-amino)-2-(syn)-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 10);

(S)-N-1-(1-(S)-Benzyl-2-(syn)-hydroxyl-3-(isobutyl-(5-pyridin-2-yl-thiophene-2-sulfonyl)-amino)-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 12);

(S)-N-1-(3-((4-Benzenesulfonyl-thiophene-2-sulfonyl)-isobutyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 13);

(S)-N-1-(1-(S)-Benzyl-3-((4-fluoro-benzenesulfonyl)-isobutyl-amino)-2-(syn)-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 14);

(S)-N-1-(3-((4-Acetylamino-3-fluoro-benzenesulfonyl)-isobutyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 15);

(S)-N-1-(3-((3-Acetylamino-4-fluoro-benzenesulfonyl)-isobutyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 16);

(S)-N-1-(1-(S)-Benzyl-3-((4-acetylamino-benzenesulfonyl)-isobutyl-amino)-2-(syn)-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 17);

(S)-N-1-(3-((5-Acetylamino-3-methyl-thiophene-2-sulfonyl)-isobutyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 18);

(S)-N-1-(3-((3-Acetylamino-benzenesulfonyl)-isobutyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 19);

(S)-N-1-(3-((Benzo(1,2,5)oxadiazole-4-sulfonyl)-isobutyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 20);

N-1-((1S-2syn)-1-Benzyl-2-hydroxy-3-(1-isobutyl-3,3-dimethylsulfonylurea)-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 21);

N-1-(3-((4-Acetylamino-benzenesulfonyl)-isobutyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-(pyridin-2-yl-methoxycarbonyl)-succinamide(compound 22);

N-1-(3-((4-Acetylamino-benzenesulfonyl)-isobutyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-(pyridin-4-yl-methoxycarbonyl)-succinamide(compound 23);

N-1-(3-((4-Fluoro-benzenesulfonyl)-isobutyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-(pyridin-2-yl-methoxycarbonyl)-succinamide(compound 26);

4-Fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 35);

3,4-Dichloro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 37);

N-(4-(((2syn,3S)-2-Hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 44);

2,4-Dimethyl-thiazole-5-sulfonicacid-(1,1-dimethyl-ethoxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-isobutyl-amide (compound 46);

N-(4-(((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 48);

4-Fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamideand 4-Fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compounds 52);

Benzo(1,2,5)oxadiazole-5-sulfonic acid ((2syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-isobutylamide(compound 66);

N-(4-(((2syn,3S)-2-Hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-sulfamoyl-phenyl)-acetamideand N-(4-(((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compounds 86);

N-(2-Fluoro-5-(((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 88);

N-(3-(((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 91);

4-Fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 93);

N-(4-(((syn)-2-Hydroxy-(S)-4-phenyl-3-((tetrahydro-furan-(R)-3-yl)-oxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 94);

4-Fluoro-N-(2syn,3S)-2-hydroxy-4-phenyl-3-((tetrahydro-furan-(R)-3-ylmethoxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamideand 4-Fluoro-N-(2syn,3S)-2-hydroxy-4-phenyl-3-((tetrahydro-furan-(S)-3-ylmethoxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compounds 97);

4-Fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 98);

4-Chloro-N-((2syn,3S)-2-hydroxy-4-phenyl-3((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-benzenesulfonamide(compound 99);

N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-4-methoxy-benzenesulfonamide(compound 100);

4-Fluoro-N-(2-(syn)-hydroxy-3-((2-oxazolidon-(S)-4-yl)-methoxycarbonylamino)-4-(S)-phenyl-butyl)-N-isobutyl-benzenesulfonamide(compound 109);

Benzene-1,3-disulfonic acid 1-amide 3-((2syn,3S)-2-hydroxy-4-phenyl-3-(3-(S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide(compound 112);

Furan-3-sulfonic acid (2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide(compound 113);

N-((3-Allyloxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-N-cyclopentylmethyl-4-fluoro-benzenesulfonamide(compound 114);

N-Cyclopentylmethyl-N-((3-ethoxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-4-fluoro-benzenesulfonamide (compound115);

4-Chloro-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 116);

4-Chloro-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3yl-methoxycarbonyl)-butyl)-benzenesulfonamide(compound 118);

N-(4-(Cyclopentylmethyl-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-sulfamoyl)-phenyl)-acetamide(compound 125);

3-Chloro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 138);

4-Chloro-N-cyclopentylmethyl-N-(2-(syn)-hydroxy-3-((2-oxazolidon-4-(S)-yl-methyl)-oxycarbonylamino)-4-phenyl-butyl)-benzenesulfonamide(compound 139);

N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-methoxy-benzenesulfonamide(compound 140);

N-((3-allyloxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-N-cyclopentylmethyl-4-methoxy-benzenesulfonamide(compound 141);

N-Cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(3-pyridin-3-yl-methoxycarbonylamino)-butyl-4-methoxy-benzenesulfonamide(compound 142);

Pyridine-3-sulfonic acid ((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide,trifluoroacetic acid salt (compound 144);

5-Isoxazol-3-yl-thiophene-2-sulfonic acid ((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide(compound 145);

N-(4-((3-(Allyloxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-cyclopentylmethylsulfamoyl)-phenyl)-acetamide(compound 146);

N-(4-(Cyclopentylmethyl-((2syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-sulfamoyl)-phenyl)-acetamide(compound 147);

N-Cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 148);

Pyridine-3-sulfonic acid cyclopentylmethyl-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-amide(compound 149);

Piperidine-1-sulfonic acid ((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide(compound 150);

N-4-((2-(syn)-Hydroxy-3-((2-methoxymethyl-allyloxycarbonylamino)-4-(S)-phenyl-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 155);

1-Acetyl-2,3-dihydro-1H-indole-6-sulfonic acid((allyloxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-cyclopentylmethyl-amide (compound156);

1-Acetyl-2,3-dihydro-1H-indole-6-sulfonic acid cyclopentylmethyl-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-amide(compound 157);

N-Cyclohexylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-methoxy-benzenesulfonamide(compound 158);

N-Cyclohexylmethyl-4-fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 159);

N-(4-(Cyclohexylmethyl)-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-sulfamoyl-phenyl)-acetamide(compound 160);

N-((2syn,3S)-2-Hydroxy-4-phenyl-3-(pyridin-4-yl-methoxycarbonylamino)-butyl)-N-isobutyl-4-methoxy-benzenesulfonamide(compound 163);

N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((syn)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-4-methyl-benzenesulfonamide(compound 165);

N-cyclopentylmethyl-4-hydroxy-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-benzenesulfonamide(compound 166);

N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-4-nitro-benzenesulfonamide(compound 167);

4-Amino-N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 168);

N-Cyclopentylmethyl-4-hydroxy-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 169);

N-Cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-nitro-benezensulfonamide(compound 170);

4-Amino-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 171);

2,4-Diamino-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 173);

4-Hydroxy-N-(2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 175);

N-Cyclopentylmethyl-4-fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 182);

3,4-Dichloro-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 183);

Benzyloxycarbonyl-(L)-isoleucine-N-(5-((3-amino-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-isobutyl-sulfamoyl)-2-fluoro-phenyl)-acetamide(compound 187);

N-((2syn,3S)-4-Cyclohexyl-2-hydroxy-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-cyclopentylmethyl-4-methoxy-benzenesulfonamide(compound 195);

and compounds 1001 through 1015.

More preferred compounds of this invention are:

(S)-N-1-(1-(S)-Benzyl-2-(syn)-hydroxyl-3-(isobutyl-(5-pyridin-2-yl-thiophene-2-sulfonyl)-amino)-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 12);

(S)-N-1-(1-(S)-Benzyl-3-((4-fluoro-benzenesulfonyl)-isobutyl-amino)-2-(syn)-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 14);

(S)-N-1-(3-((4-Acetylamino-3-fluoro-benzenesulfonyl)-isobutyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 15);

(S)-N-1-(3-((Benzo(1,2,5)oxadiazole-4-sulfonyl)-isobutyl-amino)-(1S,2syn)-1-benzyl-2-hydroxy-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 20);

N-1-((1S-2syn)-1-Benzyl-2-hydroxy-3-(1-isobutyl-3,3-dimethylsulfonylurea)-propyl)-2-((quinoline-2-carbonyl)-amino)-succinamide(compound 21);

N-(4-(((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 48);

N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-4-methoxy-benzenesulfonamide(compound 100);

4-Chloro-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 116);

N-Cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-methoxy-benzenesulfonamide(compound 140);

N-Cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(3-pyridin-3-yl-methoxycarbonylamino)-butyl-4-methoxy-benzenesulfonamide(compound 142);

N-Cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 148);

N-Cyclohexylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-methoxy-benzenesulfonamide(compound 158);

N-(4-(Cyclohexylmethyl)-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-sulfamoyl-phenyl)-acetamide(compound 160);

N-cyclopentylmethyl-4-hydroxy-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-benzenesulfonamide(compound 166);

4-Amino-N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 168);

4-Amino-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 171);

2,4-Diamino-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 173);

4-Hydroxy-N-(2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 175); and

N-((2syn,3S)-4-Cyclohexyl-2-hydroxy-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-cyclopentylmethyl-4-methoxy-benzenesulfonamide(compound 195).

The sulfonamides of this invention may be synthesized using conventionaltechniques. Advantageously, these compounds are conveniently synthesizedfrom readily available starting materials.

The compounds of this invention are among the most readily synthesizedHIV protease inhibitors known. Previously described HIV proteaseinhibitors often contain four or more chiral centers, numerous peptidelinkages and/or require air-sensitive reagents (such as organometalliccomplexes) to effect their synthesis. The relative ease with which thecompounds of this invention can be synthesized represents an enormousadvantage in the large scale production of these compounds.

In general, sulfonamides of formula I are conveniently obtained fromα-amino acid derivatives having the general formula A--(B)_(x)--NH--CH(D)--COOH, wherein A, B, X and D are defined as above for thecompounds of formula I. Such α-amino acid derivatives are oftencommercially available or may be conveniently prepared from commerciallyavailable α-amino acid derivatives using known techniques. See, forexample, T. W. Greene and P. G. M. Wuts, "Protective Groups in OrganicSynthesis", 2nd Ed., John Wiley and Sons (1991). Although this inventionenvisions the use of racemic mixtures of such starting materials, whenx=0, a single enantiomer in the S configuration is preferred.

Using known techniques, the α-amino acid derivative of general formulaA--(B)_(x) --NH--CH(D)--COOH may be readily converted to an amino ketonederivative of general formula A--(B)_(x) --NH--CH(D)--CO--CH₂ --X,wherein X is a leaving group which suitably activates the α-carbon(i.e., makes the methylene susceptible to nucleophilic attack). Suitableleaving groups are well known in the art and include halides andsulfonates, such as methanesulfonate, trifluoromethanesulfonate or4-toluenesulfonate X may also be a hydroxyl which is converted in situto a leaving group (e.g. by treatment with a trialkyl- ortriarylphosphine in the presence of a dialkylazodicarboxylate). Methodsfor the formation of such amino ketone derivatives also are well knownto those of skill in the art (see, for example, S. J. Fittkau, J. Prakt.Chem., 315, p. 1037 (1973)). Alternatively, certain amino ketonederivatives are commercially available (e.g., from Bachem Biosciences,Inc., Philadelphia, Pa.).

The amino ketone derivative may then be reduced to the correspondingamino alcohol, represented by the formula A--(B)_(x)--NH--CH(D)--CH(OH)--CH₂ --X. Many techniques for reduction of aminoketone derivatives such as A--(B)_(x) --NH--CH(D)--CO--CH₂ --X are wellknown to those of ordinary skill in the art (Larock, R. C."Comprehensive Organic Transformations", pp. 527-547, VCH Publishers,Inc.© 1989 and references cited therein). A preferred reducing agent issodium borohydride. The reduction reaction is conducted at a temperatureof from about -40° C. to about 40° C. (preferably, at about 0° C. toabout 20° C.), in a suitable solvent system such as, for example,aqueous or neat tetrahydrofuran or a lower alcohol, such as methanol orethanol. Although this invention envisions both stereospecific andnon-stereospecific reduction of the amino ketone derivative A--(B)_(x)--NH--CH(D)--CO--CH₂ --X, stereoselective reduction is preferred.Stereoselective reduction may be accomplished by use of chiral reagentsknown in the art. In the present invention, stereoselective reductionmay be conveniently achieved, for instance, under non-chelating reducingconditions, where chiral induction of the newly formed hydroxyl group isset by the stereochemistry of the D group (i.e., Felkin-Ahn addition ofhydride). We particularly prefer stereoselective reductions wherein theresulting hydroxyl is syn to D. We have found that when the hydroxylgroup is syn to D, the final sulfonamide product is an HIV proteaseinhibitor of higher potency than the anti diastereomer.

The hydroxyl group of the amino alcohol may optionally be protected byany known oxygen protecting group (such as trialkylsilyl, benzyl, oralkyloxymethyl) to yield a protected amino alcohol having the formulaA--(B)_(x) --NH--CH(D)--C(OR⁶)--CH₂ --X, wherein R⁶ is H or any suitablehydroxy protecting group. Several useful protecting groups are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 2d Ed., John Wiley and Sons (1991).

The amino alcohol may then be reacted with a nucleophilic amine compoundto form an intermediate of formula III: ##STR649## wherein D and R⁶ areas described above, and L is either D' (as described for compounds offormula I) or hydrogen.

In a particularly advantageous synthetic scheme, simultaneous activationof the methylene and protection of the alcohol may be accomplished byforming an N-protected amino epoxide from the oxygen and its adjacentmethylene to give an intermediate of formula II: ##STR650## wherein A, Band D are as defined above for compounds of formula I. Suitable solventsystems for preparing the N-protected amino epoxide include ethanol,methanol, isopropanol, tetrahydrofuran, dioxane, dimethyl formamide andthe like (including mixtures thereof). Suitable bases for producing theepoxide include alkali metal hydroxides, potassium t-butoxide, DBU andthe like. A preferred base is potassium hydroxide.

Reaction of the N-protected amino epoxide or other suitably activatedintermediates with an amine is carried out neat, i.e. in the absence ofsolvent, or in the presence of a polar solvent such as lower alkanols,water, dimethylformamide or dimethylsulfoxide. The reaction can becarried out conveniently between about 0° C. and 120° C., preferablybetween about 20° C. and 100° C. Alternatively, the reaction may becarried out in the presence of an activating agent, such as activatedalumina in an inert solvent, preferably an ether, such as diethyl ether,tetrahydrofuran, dioxane, or tert-butyl methyl ether, conveniently fromabout room temperature to about 110° C., as described by Posner andRogers, J. Am Chem. Soc., 99, p. 8208 (1977). Other activating reagentsinclude lower trialkylaluminum species, such as triethylaluminum, ordialkylaluminum halide species, such as diethylaluminum chloride(Overman and Flippin, Tetrahedron Letters, p. 195 (1981)). Reactionsinvolving these species are conveniently carried out in inert solventssuch as dichloromethane, 1,2-dichloroethane, toluene, or acetonitrilebetween about 0° C. and about 110° C. Further methods of displacingleaving groups, or opening epoxides with amines or their equivalentssuch as azides or timethylsilyl cyanide (Gassman and Guggenheim, J. Am.Chem. Soc. 104, p. 5849 (1982)), are known and will be apparent to thoseof ordinary skill in the art.

Compounds of formulae II and III, and functionality-protectedderivatives thereof, are useful as intermediates for the preparation ofcompounds of formula I. In those cases where L represents D', compoundsof formula III may be converted to compounds of formula I by reactionwith sulfonyl-activated species to form sulfonamides, sulfonyl ureas,thiocarbamates and the like. Methods for preparing suchsulfonyl-activated species are well within the ordinary skill of theart. Typically, sulfonyl halides are used to obtain sulfonamides. Manysulfonyl halides are commercially available; others may be easilyobtained using conventional synthetic techniques (Gilbert, E. E. "RecentDevelopments in Preparative Sulfonation and Sulfation" Synthesis 1969: 3(1969) and references cited therein; Hoffman, R. V."M-Trifluoromethylbenzenesulfonyl Chloride" Org. Synth. Coll. Vol. VII,John Wiley and Sons (1990); Hartman, G. D. et. al. "4-SubstitutedThiophene-and Furan-2-sulfonamides as Topical Carbonic AnhydraseInhibitors" J. Med. Chem., 35, p. 3822 (1992) and references citedtherein. Sulfonyl ureas are usually obtained by the reaction of an aminewith sulfuryl chloride or a suitable equivalent such assulfuryl-bis-imidazole or sulfuryl-bis-N-methyl imidazole.Thiocarbamates are typically obtained by the reaction of an alcohol withsulfuryl chloride or a suitable equivalent such assulfuryl-bis-imidazole or sulfuryl-bis-N-methyl imidazole.

In the case of compounds of formula III wherein L is hydrogen,conversion of the resultant primary amine to a secondary amine may becarried out by known techniques. Such techniques include reaction withan alkyl halide of alkyl sulfonate, or by reductive alkylation with analdehyde or carboxylic acid or activated derivative thereof using, forinstance, catalytic hydrogenation or sodium cyanoborohydride (Borch etal., J. Am. Chem. Soc., 93, p. 2897 (1971)). Alternatively, the primaryamine may be acylated followed by reduction with borane or anothersuitable reducing reagent, for example, as described by Cushman et al.,J. Org. Chem., 56, p. 4161 (1991). This technique is especially usefulin compounds of formula III where B is absent and A represents aprotecting group such as tert-butoxycarbonyl (Boc) or benzyloxycarbonyl(Cbz).

If variable A of a particular compound of formula I represents aremovable protecting group, removal of that group followed by reactionof the resulting amine with an appropriate activated reagent willadvantageously yield a different compound of formula I. For instance,reaction with an activated carboxylate, such as an acyl halide (e.g.,acid fluorides, acid chlorides, and acid bromides), an activated estersuch as nitrophenyl ester or 1-hydroxysuccinimide (HOSu) ester, ananhydride such as the symmetrical anhydride or isobutyl anhydride, ormixed carbonic-phosphoric or carbonic-phosphinic anhydrides, will yieldthe corresponding amide. Ureas may be obtained by reaction withisocyanates or amines in the presence of bis-activated carbonic acidderivatives such as phosgene or carbonyldiimdazole. Carbamates may beobtained by reaction with chlorocarbonates, with carbonates esterifiedwith leaving groups such as 1-hydroxybenzotriazole (HOBT) or HOSu, orwith alcohols in the presence of bis-activated carbonic acid derivativessuch as phosgene or carbonyldiimdazole. It will be readily recognizedthat in order to facilitate specific reactions, the protection of one ormore potentially reactive groups followed by subsequent removal of thatgroup may be required. Such modification to the reaction schemesoutlined above are within the ordinary skill of the art.

If variable B of a particular compound of formula I is absent andvariable A of that compound represents a removable protecting group,removal of A, followed by reaction of the resulting amine with an aminoacid or suitably N-protected derivative thereof, followed by asubsequent reaction of the free α-amine if present, as described above,will yield a further compound of formula I. The addition of amino acidsand their derivatives is accomplished by well known methods of peptidesynthesis. Some of these methods are generally set forth in Bodanszkyand Bodanszky, "The Practice of Peptide Synthesis", Springer-Verlag,Berlin, Germany (1984) and in the "The Peptides", Gross and Meinhofer(Eds); Academic Press, 1979, Vols. I-III, which are incorporated hereinby reference.

Typically, for solution phase synthesis of peptides, the α-amine of theamino acid to be coupled is protected by Boc, Cbz, allyloxycarbonyl(Alloc) or 9-fluorenylmethoxycarbonyl (Fmoc), while the free carboxyl isactivated by reaction with a carbodiimide such asdicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), ordiisopropylcarbodiimide (DIC), optionally in the presence of a catalystsuch as HOBT, HOSu, or dimethylaminopyridine (DMAP). Other methods whichproceed through the intermediacy of activated esters, acid halides,enzyme-activated amino acids and anhydrides includingN-carboxy-anhydrides, symmetrical anhydrides, mixed carbonic anhydrides,carbonic-phosphinic and carbonic-phosphoric anhydrides are alsosuitable. After the peptide has been formed, protecting groups may beremoved by methods described in the references listed above, such as byhydrogenation in the presence of a palladium, platinum or rhodiumcatalyst, treatment with sodium in liquid ammonia, hydrochloric,hydrofluoric, hydrobromic, formic, trifluoromethanesulfonic, ortrifluoroacetic acid, secondary amines, fluoride ion, trimethylsilylhalides including bromide and iodide, or alkali.

One particularly useful synthetic scheme for producing sulfonamides offormula XV is shown below: ##STR651##

Compounds of formula X may be advantageously synthesized from readilyavailable starting materials (see D. P. Getman, J. Med. Chem., 36, p.288 (1993)). Each step of the above synthetic scheme may be carried outas generally described above.

A particularly useful synthetic scheme for producing the preferredsulfonamides of formula XXII is shown below: ##STR652##

Compounds of formula XX may be advantageously synthesized from readilyavailable starting materials (see B. E. Evans et al., J. Org. Chem., 50,p. 4615 (1985)). Each step of the above synthetic scheme may be carriedout as generally described above.

After converting a compound of formula XX to a compound of formula XXI,as detailed in the previous reaction scheme, the compound of formula XXImay alternatively be reacted with an amino acid or amino acidderivative, as described generally above, to yield a preferred compoundof formula XXXI. A particularly useful synthetic scheme utilizing thisstrategy is set forth below: ##STR653##

As can be appreciated by the skilled artisan, the above syntheticschemes are not intended to comprise a comprehensive list of all meansby which the compounds described and claimed in this application may besynthesized. Further methods will be evident to those of ordinary skillin the art.

The compounds of this invention may be. modified by appendingappropriate functionalites to enhance selective biological properties.Such modifications are known in the art and include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds of formula I are characterized by a superior ability toinhibit HIV protease activity and viral replication. We believe thatthis is due to specific steric and electronic interactions between theprotease and compounds of formula I. This belief stems from our analysisof the structural basis for the activity of compounds of formula I, inview of the known crystal structures of HIV protease and boundinhibitors, such as the structure reported in Miller et al. "Structureof Complex of Synthetic HIV-1 Protease with a Substrate-Based Inhibitorat 2.3 Å Resolution", Science, vol. 246, pp. 1149-1152 (1989), which isincorporated herein by reference, as well as structures determined inour laboratories. According to these structures, the active site of HIVaspartyl protease is defined by a deep groove containing subpockets foraccommodation of various side chains of the protease substrate--referredto as P₁ -P_(n) and P₁ '-P_(n) ', according to conventional proteasenomenclature. In the center of the groove, lie two aspartic acidresidues (Asp25 and Asp25' according to the numbering system of Milleret al.) in a manner typical of the active site aspartates of knownaspartyl proteases, which are believed to be the catalytic residues ofthe enzyme. The groove is covered by two C₂ -symmetrically disposed"flaps" which also make various direct and indirect contacts with boundsubstrates.

We believe that the substituents A, D, D' and E of the compounds offormula I associate with HIV protease by way of hydrophobic forces inthe binding pockets of the enzyme. We also believe that the sulfonamidegroup hydrogen binds tightly to a water molecule held by hydrogen bondsto the flaps of the protease ("the flap water molecule"; water molecule511, according to the Miller et al. numbering system).

In view of the above discovery, an alternative embodiment of thisinvention relates to novel HIV protease inhibitors possessing certainstructural and physicochemical features. We have discovered thatcompounds possessing the following novel combination of features aresurprisingly effective HIV protease inhibitors:

(1) a first and a second hydrogen bond acceptor moiety, at least one ofwhich is more highly polarizable than a carbonyl, said moieties beingthe same or different, and being capable of hydrogen bonding with thehydrogen atoms of the flap water molecule of an HIV aspartyl proteasewhen the compound is bound thereto;

(2) substantially hydrophobic moieties which associate with the P₁ andP₁ ' binding pockets of said HIV aspartyl protease when the compound isbound thereto;

(3) a third hydrogen bonding moiety, which may be either a hydrogen bonddonor or acceptor, capable of simultaneously hydrogen bonding to Asp25and Asp25' of said HIV aspartyl protease when the compound is boundthereto;

(4) an additional occupied volume of space of at least 100 Å³ when thecompound is bound to the active site of said HIV aspartyl protease, saidspace overlapping with the volume of space that would be filled by anative substrate of said HIV aspartyl protease or a nonhyrolyzableisostere thereof;

(5) a deformation energy of binding of the compound to said HIV aspartylprotease of not greater than 10 kcal/mole; and

(6) a neutral or favorable enthalpic contribution from the sum of allelectrostatic interactions between the compound and the protease whenthe compound is bound to said HIV aspartyl protease.

Compounds having the above-cited features can be readily identified ordesigned by one of ordinary skill in the art using a combination ofchemical reasoning and computational methods. For example, those ofordinary skill in the art can readily identify or choose hydrogenbonding and hydrophobic moieties or groups required in features (1)-(3),while features (4)-(6) can be ascertained using well known computationalmethods for determination of structural (e.g. conformational) andenergetic properties of molecules.

Furthermore, compounds characterized by features (1) through (6) listedabove may be obtained using any conventional technique, includingchemical synthesis and natural product isolation. We prefer using thesynthetic schemes detailed above for compounds of formula I.

We have discovered that when an HIV protease inhibitor forms hydrogenbonds to the flap water molecule through two hydrogen bonding moieties,at least one of which is more highly polarizable than a carbonyl, theability of those compounds to inhibit HIV protease activity isdramatically improved, as compared with conventional HIV proteaseinhibitors.

While not wishing to be bound by theory, we believe that the stronghydrogen bonds that form between the flap water molecule and the twohydrogen bonding moieties, at least one of which is more highlypolarizable than a carbonyl, lower the overall binding energy of theinhibitor. Most HIV protease inhibitors known in the art utilize onlycarbonyl groups for hydrogen bonding to the flap water molecule and are,thus, inferior to those of the present invention. We believe that theincreased polarization that results from the large dipole moment of thehighly polarizable hydrogen bonding moiety (as compared to the dipolemoment of a carbonyl moiety) creates a stronger and tighter hydrogenbond with the flap water molecule. We prefer to utilize tetravalentoxygenated sulfur, hexavalent oxygenated sulfur and pentavalentoxygenated phosphorus as the highly polarizable hydrogen bonding moiety.Tetravalent oxygenated sulfur and hexavalent oxygenated sulfur are morepreferred as the highly polarizable hydrogen bonding moiety. Hexavalentoxygenated sulfur (--SO₂ --) is most preferred.

We have found that when the highly polarizable hydrogen bonding moietyis a sulfonamide, the overall binding energy of the inhibitor isparticularly low. We believe that this increased stability is due toparticular conformational characteristics of the sulfonamide S--N bond.Specifically, the sulfonamide S--N bond exists in only two low-energyrotamers (see J. B. Nicholas et al., J. Phys. Chem., 95, p. 9803 (1991)and R. D. Bindal et al., J. Am. Chem. Soc., 112, p. 7861 (1990)). Thishas the effect of locking that portion of the molecule into a favorableconformation wherein one or both of the highly polarized S═O oxygens canbe involved in hydrogen bonding interactions with the flap water.

The remaining five structural and physicochemical features recited above(i.e., features (2) through (6)) are generally recognized in the art toimprove the ability of a compound to competitively inhibit HIV proteaseactivity. Although there are several other features thought to increasethe inhibitory property (such as binding of the inhibitor backbone tothe enzyme), we have discovered that the combination of the fiveabove-cited elements alone, together with novel element (1), typifieseffective HIV protease inhibitors.

In general, the binding energy of a particular protease inhibitor islowered when hydrophobic moieties on the inhibitor are located so as toassociate with the enzyme's hydrophobic binding pockets. In the case ofHIV-1 protease, the location and nature of the P₁ and P₁ ' bindingpockets are known to those of ordinary skill in the art (see, forexample, M. Miller et al., cited above). Substantially hydrophobic sidechains which fit into the well defined P₁ and P₁ ' binding pockets arealso known to those in the art. Preferred side chains are located within4 Å of the enzyme when bound to HIV protease. Preferred hydrophobic sidechains include those substantially similar to those of hydrophobicnatural and unnatural α-amino acids, including alanine, valine, leucine,isoleucine, methionine, phenylalanine, α-amino isobutyric acid,alloisoleucine, tyrosine, and tryptophan. Insofar as a portion of thisside chain is in contact with bulk solvent or protrudes out of theenzyme, it is not considered to be wholly within P₁ or P₁ ' and maycontain polar functionality such as a charged amine at that location.

It has also been established in the art that the presence of a hydroxylgroup within hydrogen bond proximity to the two catalytic aspartic acidresidues of HIV protease (Asp25 and Asp25') is an important feature ofan effective HIV protease inhibitor (see, for example, R. Bone et al.,"X-ray Crystal Structure of the HIV Protease Complex with L-700,417, anInhibitor with Pseudo C₂ Symmetry", J. Am. Chem. Soc., 113, pp. 9382-84(1991)). It is further understood that the geometry of the Asp-bindinghydrogen bonding moiety is of particular importance. Although we preferto use a hydroxyl group at this position, any hydrogen bonding moietythat is capable of forming hydrogen bonds with the Asp residues isacceptable. Such hydrogen bonding moieties are known to those of skillin the art (e.g., phosphinic acid (D. Grobelny et al., Biochem. Biophys.Res. Commun., 169, p. 1111 (1990)).

It is further understood that binding of competitive inhibitors to HIVprotease is optimally accomplished by having the inhibitor traverse avolume overlapping that occupied by the native polypeptide substratewhen it is bound to the active site of the enzyme. Effective HIVprotease inhibitors typically have a relatively small difference inenergy between their bound and free states (i.e., a small deformationenergy of binding). The most preferred HIV protease inhibitors of thisinvention have a deformation energy of binding of not greater than 10kcal/mole (preferably, not greater than 7 kcal/mole). It should benoted, however, that HIV protease inhibitors may interact with HIVprotease in more than one conformation which is similar in overallbinding energy (see K. H. M. Murthy, J. Biol. Chem., 267, (1992)). Inthose cases, the deformation energy of binding is taken to be thedifference between the energy of the free compound and the averageenergy of the conformations observed when the inhibitor binds to theenzyme.

Furthermore, it is understood that the most effective proteaseinhibitors also lack repulsive electrostatic interaction with the targetprotease in their bound state. Such non-complementary (e.g.,electrostatic) interactions include repulsive charge-charge,dipole-dipole and charge-dipole interactions. Specifically, in the mostpreferred HIV protease inhibitors of this invention, the sum of allelectrostatic interactions between the compound and the enzyme when thecompound is bound to HIV protease makes a neutral or favorablecontribution to the enthalpy of binding.

Preferred compounds characterized by the above features (1)-(6) arecompounds of formula XL:

    Z.sup.1 --Q.sup.1 --L.sup.1 --M--L.sup.2 --Q.sup.2 --Z.sup.2(XL)

wherein:

Q¹ and Q² are independently hydrogen bond acceptor moieties capable ofbinding with the hydrogen atoms of the flap water molecule of an HIVaspartyl protease, with the proviso that at least one of Q¹ or Q² ismore highly polarizable than a carbonyl;

M is a hydrogen bonding moiety, which may be either a hydrogen bonddonor or acceptor, capable of simultaneously hydrogen bonding to Asp25and Asp25' of said HIV aspartyl protease;

L¹ and L² are independently acyclic or cyclic linker moieties; and

each of Z¹ and Z² may be optionally present and, if present, areindependently selected from groups which occupy a volume of spaceoverlapping with the volume of space that would be filled by the nativesubstrate of said HIV aspartyl protease.

More preferred compounds of formula XL contain at least one group Q¹ orQ² comprising --SO₂ --. Most preferrred compounds of formula XL containat least one group Q¹ or Q² comprising a substituted sulfonamide.

In one embodiment of this invention, compounds of formula XL may befurther constrained by "conformational locks", such as a macrocyclicring structure. Such constraints are well known in the art ofpeptidomimetics and may result in compounds with strong biologicalactivity. See, for example, Dhanoa, D. S. et al. "The Synthesis ofPotent Macrocyclic Renin Inhibitors" Tetrahedron Lett. 33, 1725 (1992)and Flynn, G. A. et al. "An Acyl-Iminium Ion Cyclization Route to aNovel Conformationally Restricted Dipeptide Mimic: Applications toAngiotensin-Converting Enzyme Inhibition" J. Am. Chem. Soc. 109, 7914(1989)).

This invention also includes novel methods for accurate identification,design, or prediction of HIV inhibitors characterized by structural andphysicochemical features (1) through (6). By virtue of these methods,the skilled artisan can routinely predict and produce particularlyeffective HIV protease inhibitors.

We have found that the following method for identification, design orprediction of effective HIV protease inhibitors is particularly useful;

(a) selecting a candidate compound of defined chemical structurecontaining a first and a second hydrogen bond acceptor moiety, at leastone of which is more highly polarizable than a carbonyl, said moietiesbeing the same or different; a third hydrogen bonding moiety, which maybe either a hydrogen bond donor or acceptor; and at least twosubstantially hydrophobic moieties;

(b) determining a low-energy conformation for binding of said compoundto the active site of an HIV aspartyl protease;

(c) evaluating the capability of said first and second hydrogen bondacceptor moieties to form hydrogen bonds to the flap water molecule ofsaid HIV aspartyl protease when said compound is bound thereto in saidconformation;

(d) evaluating the capability of said substantially hydrophobic moietiesto associate with the P₁ and P₁ ' binding pockets of said HIV aspartylprotease when said compound is bound thereto in said conformation;

(e) evaluating the capability of said third hydrogen bonding moiety toform hydrogen bonds to Asp25 and Asp25' of said HIV aspartyl proteasewhen said compound is bound thereto in said conformation;

(f) evaluating the overlap of the occupied volume of said compound whensaid compound is bound to said HIV aspartyl protease in saidconformation and the occupied volume of a native substrate of HIVaspartyl protease or a nonhydrolyzable isostere thereof, when saidpolypeptide is bound to said HIV aspartyl protease;

(g) evaluating the deformation energy of binding of said compound tosaid HIV aspartyl protease;

(h) evaluating the enthalpic contribution of the sum of allelectrostatic interactions between said compound and said HIV aspartylprotease when said compound is bound thereto in said conformation; and

(i) accepting or rejecting said candidate compound as an HIV proteaseinhbitor based upon the determinations and evaluations carried out insteps (b) through (h).

Using the novel combination of steps set forth in this screening method,the skilled artisan can advantageously avoid time consuming andexpensive experimentation to determine enzymatic inhibition activity ofparticular compounds. The method is also useful for facilitatingrational design of HIV protease inhibitors and anti-HIV viral agents,including therapeutic and prophylactic agents against HIV infection.Accordingly, the present invention relates to such inhibitors andanti-viral agents produced by the screening method described above.

A variety of conventional techniques may be used to carry out each ofthe above evaluations. Generally, these techniques involve determiningthe location and binding proximity of a given moiety, the occupiedvolume of space of a bound compound, the deformation energy of bindingof a given compound and electrostatic interaction energies. Examples ofconventional techniques useful in the above evaluations include: quantummechanics, molecular mechanics, molecular dynamics, Monte Carlosampling, systematic searches and distance geometry methods (G. R.Marshall, Ann. Ref. Pharmacol. Toxicol., 27, p. 193 (1987)). Specificcomputer software has been developed for use in carrying out thesemethods. Examples of programs designed for such uses include: Gaussian92, revision C (M. J. Frisch, Gaussian, Inc., Pittsburgh, Pa. ©1992);AMBER, version 3.0 (U. C. Singh, University of California at SanFrancisco, ©1992); QUANTA/CHARMM (Molecular Simulations, Inc.,Burlington, Mass. ©1992); and Insight II/Discover (Biosysm TechnologiesInc., San Diego, Calif. ©1992). These programs may be implemented, forinstance, using a Silicon Graphics workstation, IRIS 4D/35 or IBMRISC/6000 workstation model 550. Other hardware systems and softwarepackages will be known and of evident applicability to those skilled inthe art.

Additional analysis of the actual detailed interactions of the HIVprotease-inhibitor complex can be employed to ascertain morespecifically the binding associations between the enzyme and the boundinhibitor. Such analysis may be carried out, for example, by studying asolution of the complex by single- and multi-dimensional NMR techniques.Advantageously, the enzyme and/or the inhibitor may be enriched withstable isotopes such as ¹³ C, ¹⁵ N and ² H to more easily determinebinding conformation and proximity. Techniques, such as isotope editing,may be used to enhance the resolution with which the interactions areobserved.

Either as an alternative or a supplemental analysis, the HIVprotease-inhibitor complex may be studied by single crystal X-raydiffraction. The process of determining the structures ofprotein/inhibitor complexes using the X-ray techniques described aboveis well known and has been used for many different complexes (see T. L.Blundel and L. N. Johnson, Protein Crystallography, Academic Press,(1976) and Methods in Enzymology, volumes 114 and 115, H. W. Wyckoff etal., eds., Academic Press (1985)). This technique can employ, forinstance, a highly purified preparation of HIV protease complexed withan inhibitor of interest in a buffered solution (typically at a pH ofbetween about 4.5 and about 8.0). The complex is allowed to crystallizein the presence of a precipitation agent (such as ammonium sulfate)under conditions which yield single crystals of the complex. Specificconditions for crystallizing HIV protease with various inhibitors havebeen well documented (see, for example, G. B. Dreyer et al.,Biochemistry, 31, p. 6646 (1992)). Application of a concentrated X-raybeam to an appropriately prepared and mounted crystal (preferably, anX-ray beam from a rotating anode X-ray generator or synchrotron) willyield a diffraction pattern from the reflected X-ray beam.

Detection of the diffracted rays may be carried out by visualizingphotographic paper exposed to the diffracted X-rays or alternatively, byusing a multiwire area detector (such as that manufactured by SiemensAnalytical X-Ray Instruments, Inc. (Madison, Wis.)) or an R-axis IIimage plate system from Rigaku Corporation (distributed by MolecularStructure Corporation, The Woodlands, Tex.). Other systems forgenerating and collecting X-ray diffraction data will be known to thoseof ordinary skill in the art.

Refinement of the X-ray diffraction data yields a three dimensionalstructure. Computer software (such as X-PLOR (Yale University, ©1992,distributed by Molecular Simulations, Inc.) has been developed to carryout this refinement.

In general, using the above techniques with an appropriately preparedcrystalline complex, a structure may be refined to about 2-3 Å with an Rvalue of about 0.25 or less. As the skilled artisan can appreciate,these values are adequate to determine the interactions between HIVprotease and a given compound such that it will be clear if features (1)through (6) are present and consequently, whether that given compound isan HIV aspartyl protease inhibitor. Thus, additional inhibitorsaccording to this invention may be designed and predicted based on acombination of crystallographic structural information and computationalanalysis.

For example, to predict the binding of a candidate inhibitor accordingto this invention, the inhibitor is examined to determine whether themolecule contains functionality which is not well represented by theexisting forcefield models in CHARMM (Molecular SimulationsIncorporated, Burlington, Mass.) or AMBER (Professor P. A. Kollman,UCSF). If any functionality is not well represented, we then examine allpublished structural information for molecules containing suchfunctionality, and in some cases perform high-level ab initiocalculations on simple molecules containing these functionalities todetermine their preferred conformations and the energy differencesbetween various conformations. More accurate parameters describing thesefunctional groups may then be derived for the CHARMM and/or AMBERforcefields and used in subsequent calculations.

Next, the candidate inhibitor is aligned in 3-dimensional space withother, related inhibitors whose bound conformations have previously beendetermined by x-ray crystallography. Both Van der Walls volume andelectrostatic potentials are used to direct the alignment process. Thealignment is typically done with software like Quanta (MolecularSimulations) or InsightII (Biosym Technologies, San Diego, Calif.). Thisalignment can be done manually within this software, or more automatedalignment procedures within the software (e.g. the "superimpose" optionof Quanta or the "APEX" module of InsightII) may be used. The result ofthis alignment is a first guess of the "bound" conformation of thecandidate inhibitor. This inhibitor is then docked in the active site ofHIV protease, and the confomation is energy minimized with the enzymeatoms held fixed in space. These minimizations are typically done usingthe CHARMM or AMBER forcefields.

Because inhibitors can sometimes bind in multiple or unexpectedconformations within an active site, we often then carry out furthersearches of the bound conformation of the enzyme-inhibitor complex. Forexample, a variety of Monte Carlo search techniques (e.g. as found inthe Conformational Search Module of Quanta) may be used, along withhigh-temperature dynamics and simulated annealing. These searchtechniques reveal whether there are alternative, reasonable low-energyconfomrations in which the inhibitor may bind to the enzyme. The effectsof solvation and desolation in the formation of the variousenzyme-inhibitor complexes may be estimated with programs such as DELPHI(Biosym), Polaris (Molecular Simulations) and AMSOL (Professor C.Cramer, University of Minnesota). The result of this searching is a setof one or more bound conformations for the candidate inhibitor.

For each of the low-energy conformations, waters may then be added tothe active site of the enzyme and the entire system relaxed. Finally,molecular dynamics simulations may be used to study the detailed motionsof the enzyme, the inhibitor, and related water molecules.

The final set of remaining low-energy conformations (typically a verysmall number) represents our predictions of the bound conformation ofthe candidate inhibitor. Each conformation includes our estimate of thedynamic flexibility of the entire system (inhibitor, enzyme, andwaters).

The more advanced methodology is typically applied to the study of thefirst few compounds in a series, when there are the greatestuncertainties about the possible binding mode(s) in the enzyme activesite. For later compounds within a series, the low energy conformersobtained from the searches on earlier compounds provide informationabout the possible low energy conformers of the inhibitor compounds. Inaddition, crystallographic information about the conformation of thebound complexes of earlier compounds within a series is often available.This prior computational and structural work advantageously facilitatesthe prediction of the bound conformation of candidate inhibitormolecules.

To exemplify the above screening method, we have carried out thefollowing evaluation of compound 140 (Table II), a preferred compound ofthis invention, as described below.

Prediction of Binding Conformation and Energy of Compound 140 to HIVProtease

The forcefield for the benzenesulfonamide portion of compound 140 wasderived from ab initio calculations and incorporated into the AMBERforcefield. The latest CHARMM forcefield parameters for this moiety werefound to be adequate for energy minimization studies and are used in allQuanta/CHARMM calculations.

The low energy conformers obtained from the conformational searches onearlier compounds in the sulfonamide series (such as compound 16)provided information about the possible low energy conformers ofcompound 140. These low energy conformers were aligned in 3-dimensionalspace with other related inhibitors whose bound conformations havepreviously been determined by x-ray crystallography. This alignmentprocess was carried out manually within Quanta and, in some cases, wasassisted with the "conformational search" option of Quanta. Thereference crystal structure used in this alignment was the complex ofHIV-1 protease with compound 16. This inhibitor structure was energyminimized in the active site of the enzyme using Quanta/CHARM. Theenzyme atoms were held fixed during this minimization. only the flapwater was included. Later simulations allowed the enzyme to relax andused a variety of dielectric approximations. A single low-energyconformation which was consistent with all previous conformationalsimulations and crystallographic data was obtained (see FIG. 1). Thispredicted binding conformation was later found to be essentially inagreement with the results obtained by x-ray crystallography (see FIGS.2 and 3).

As discussed above, the novel compounds of the present invention areexcellent ligands for aspartyl proteases, particularly HIV-1 and HIV-2proteases. Accordingly, these compounds are capable of targeting andinhibiting late stage events in HIV replication, i.e., the processing ofthe viral polyproteins by HIV encoded proteases. Such compounds inhibitthe proteolytic processing of viral polyprotein precursors by inhibitingaspartyl protease. Because aspartyl protease is essential for theproduction of mature virions, inhibition of that processing effectivelyblocks the spread of virus by inhibiting the production of infectiousvirions, particularly from chronically infected cells. Compoundsaccording to this invention advantageously inhibit the ability of theHIV-1 virus to infect immortalized human T cells over a period of days,as determined by an assay of extracellular p24 antigen--a specificmarker of viral replication. Other anti-viral assays have confirmed thepotency of these compounds.

The compounds of this invention may be employed in a conventional mannerfor the treatment of viruses, such as HIV and HTLV, which depend onaspartyl proteases for obligatory events in their life cycle. Suchmethods of treatment, their dosage levels and requirements may beselected by those of ordinary skill in the art from available methodsand techniques. For example, a compound of this invention may becombined with a pharmaceutically acceptable adjuvant for administrationto a virally-infected patient in a pharmaceutically acceptable mannerand in an amount effective to lessen the severity of the viralinfection.

Alternatively, the compounds of this invention may be used in vaccinesand methods for protecting individuals against viral infection over anextended period of time. The compounds may be employed in such vaccineseither alone or together with other compounds of this invention in amanner consistent with the conventional utilization of proteaseinhibitors in vaccines. For example, a compound of this invention may becombined with pharmaceutically acceptable adjuvants conventionallyemployed in vaccines and administered in prophylactically effectiveamounts to protect individuals over an extended period time against HIVinfection. As such, the novel protease inhibitors of this invention canbe administered as agents for treating or preventing HIV infection in amammal.

The compounds of formula I, especially those having a molecular weightof less than about 700 g/mole, may be readily absorbed by thebloodstream of mammals upon oral administration. Compounds of formula Ihaving a molecular weight of less than about 600 g/mole are most likelyto demonstrate oral availability. This surprisingly impressive oralavailability makes such compounds excellent agents fororally-administered treatment and prevention regimens against HIVinfection.

The compounds of this invention may be administered to a healthy orHIV-infected patient either as a single agent or in combination withother anti-viral agents which interfere with the replication cycle ofHIV. By administering the compounds of this invention with otheranti-viral agents which target different events in the viral life cycle,the therapeutic effect of these compounds is potentiated. For instance,the co-administered anti-viral agent can be one which targets earlyevents in the life cycle of the virus, such as cell entry, reversetranscription and viral DNA integration into cellular DNA. Anti-HIVagents targeting such early life cycle events include, didanosine (ddI),alcitabine (ddC), d4T, zidovudine (AZT), polysulfated polysaccharides,sT4 (soluble CD4), ganiclovir, dideoxycytidine, trisodiumphosphonoformate, eflornithine, ribavirin, acyclovir, alpha interferonand trimenotrexate. Additionally, non-nucleoside inhibitors of reversetranscriptase, such as TIBO or nevirapine, may be used to potentiate theeffect of the compounds of this invention, as may viral uncoatinginhibitors, inhibitors of trans-activating proteins such as tat or rev,or inhibitors of the viral integrase.

Combination therapies according to this invention exert a synergisticeffect in inhibiting HIV replication because each component agent of thecombination acts on a different site of HIV replication. The use of suchcombinations also advantageously reduces the dosage of a givenconventional anti-retroviral agent which would be required for a desiredtherapeutic or prophylactic effect as compared to when that agent isadministered as a monotherapy. These combinations may reduce oreliminate the side effects of conventional single anti-retroviral agenttherapies while not interfering with the anti-retroviral activity ofthose agents. These combinations reduce potential of resistance tosingle agent therapies, while minimizing any associated toxicity. Thesecombinations may also increase the efficacy of the conventional agentwithout increasing the associated toxicity. In particular, we havediscovered that these compounds act synergistically in preventing thereplication of HIV in human T cells. Preferred combination therapiesinclude the administration of a compound of this invention with AZT,ddI, ddC or d4T.

Alternatively, the compounds of this invention may also beco-administered with other HIV protease inhibitors such as Ro 31-8959(Roche), L-735,524 (Merck), XM 323 (Du-Pont Merck) and A-80,987 (Abbott)to increase the effect of therapy or prophylaxis against various viralmutants or members of other HIV quasi species.

We prefer administering the compounds of this invention as single agentsor in combination with retroviral reverse transcriptase inhibitors, suchas derivatives of AZT, or other HIV aspartyl protease inhibitors. Webelieve that the co-administration of the compounds of this inventionwith retroviral reverse transcriptase inhibitors or HIV aspartylprotease inhibitors may exert a substantial synergistic effect, therebypreventing, substantially reducing, or completely eliminating viralinfectivity and its associated symptoms.

The compounds of this invention can also be administered in combinationwith immunomodulators (e.g., bropirimine, anti-human alpha interferonantibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha,diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO); andantibiotics (e.g., pentamidine isethiorate) to prevent or combatinfection and disease associated with HIV infections, such as AIDS andARC.

When the compounds of this invention are administered in combinationtherapies with other agents, they may be administered sequentially orconcurrently to the patient. Alternatively, pharmaceutical orprophylactic compositions according to this invention may be comprisedof a combination of an aspartyl protease inhibitor of this invention andanother therapeutic or prophylactic agent.

Although this invention focuses on the use of the compounds disclosedherein for preventing and treating HIV infection, the compounds of thisinvention can also be used as inhibitory agents for other viruses whichdepend on similar aspartyl proteases for obligatory events in their lifecycle. These viruses include, as well as other AIDS-like diseases causedby retroviruses, such as simian immunodeficiency viruses, but are notlimited to, HTLV-I and HTLV-II. In addition, the compounds of thisinvention may also be used to inhibit other aspartyl proteases, and inparticular, other human aspartyl proteases, including renin and aspartylproteases that process endothelin precursors.

Pharmaceutical compositions of this invention comprise any of thecompounds of the present invention, and pharmaceutically acceptablesalts thereof, with any pharmaceutically acceptable carrier, adjuvant orvehicle. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of this inventioninclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. We prefer oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxic.pharmaceutically-acceptable carriers, adjuvants or vehicles. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intra-articular, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant such as Ph. Helv or a similar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, and aqueous suspensions and solutions. Inthe case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried corn starch. Whenaqueous suspensions are administered orally, the active ingredient iscombined with emulsifying and suspending agents. If desired, certainsweetening and/or flavoring and/or coloring agents may be added.

The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches arealso included in this invention.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

Dosage levels of between about 0.01 and about 100 mg/kg body weight perday, preferably between about 0.5 and about 50 mg/kg body weight per dayof the active ingredient compound are useful in the prevention andtreatment of viral infection, including HIV infection. Typically, thepharmaceutical compositions of this invention will be administered fromabout 1 to about 5 times per day or alternatively, as a continuousinfusion. Such administration can be used as a chronic or acute therapy.The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. A typicalpreparation will contain from about 5% to about 95% active compound(w/w). Preferably, such preparations contain from about 20% to about 80%active compound.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

As the skilled artisan will appreciate, lower or higher doses than thoserecited above may be required. Specific dosage and treatment regimensfor any particular patient will depend upon a variety of factors,including the activity of the specific compound employed, the age, bodyweight, general health status, sex, diet, time of administration, rateof excretion, drug combination, the severity and course of theinfection, the patient's disposition to the infection and the judgmentof the treating physician.

The compounds of this invention are also useful as commercial reagentswhich effectively bind to aspartyl proteases, particularly HIV aspartylprotease. As commercial reagents, the compounds of this invention, andtheir derivatives, may be used to block proteolysis of a target peptideor may be derivatized to bind to a stable resin as a tethered substratefor affinity chromatography applications. These and other uses whichcharacterize commercial aspartyl protease inhibitors will be evident tothose of ordinary skill in the art.

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

General Materials and Methods

All temperatures are recorded in degrees Celsius. Thin layerchromatography (TLC) was carried out using 0.25 mm thick E. Merck silicagel 60 F₂₅₄ plates and elution with the indicated solvent system.Detection of the compounds was carried out by treating the plate with anappropriate visualizing agent, such as 10% solution of phosphomolybdicacid in ethanol or a 0.1% solution of ninhydrin in ethanol, followed byheating, and/or by exposure to UV light or iodine vapors whenappropriate. Thick layer silica gel chromatography was also carried outusing E. Merck 60 F₂₅₄ plates ("prep plates") of 0.5, 1.0, or 2.0 mmthickness. Following development of the plate, the band of silicacontaining the desired compound was isolated and eluted with anappropriate solvent. Analytical HPLC was carried out using a Water'sDelta Pak, 5 μM silica, C18 reversed-phase column, 3.9 mm ID×15 cm Lwith a flow rate of 1.5 mL/min using the following table:

Mobile phase

A=0.1% CF₃ CO₂ H in H₂ O

B=0.1% CF₃ CO₂ H in CH₃ CN

Gradient

T=0 min., A (95%), B (5%)

T=20 min., A (0%), B (100%)

T=22.5 min., A (0%), B (100%)

Preparative HPLC was also carried out using C₁₈ reversed-phase media.HPLC retention times were recorded in minutes. NMR spectral data wasrecorded using a Bruker AMX500, equipped with either a reverse or QNPprobe, at 500 MHz, and was taken in the indicated solvent.

We have measured the inhibition constants of each compound against HIV-1protease using the method described essentially by M. W. Pennington etal., Peptides 1990, Gimet, E. and D. Andrew, Eds., Escom; Leiden,Netherlands (1990).

Compounds of formula I were tested for their antiviral potency inseveral virological assays. In the first assay, the compounds were addedas a solution in dimethylsulfoxide (DMSO) to a test cell culture ofCCRM-CEM cells, a strain of CD4⁺ human T-cell lymphoma cells, previouslyacutely infected with HIV_(IIIb) using standard protocols (see Meek, T.D. et al., "Inhibition of HIV-1 protease in infected T-lymphocytes bysynthetic peptide analogues", Nature, 343, p. 90 (1990). Preferredcompounds are those which are able to inhibit 90% of viral infectivityat a concentration of 1 μM or less. More preferred compounds are thosewhich are able to inhibit 90% of viral infectivity at a concentration of100 nM or less.

The effect of the compounds on inhibiting the replication of the viruswas measured by determining the HIV extracellular p24 antigenconcentration using a commercial enzyme immunoassay (obtained fromCoulter Corporation, Hialeah, Fla.).

Depending on the cell type and the desired readout, syncytia formation,reverse-transcriptase (RT) activity, or cytopathic effect as assayed bya dye uptake method may also be used as readouts of antiviral activity.See H. Mitsuya and S. Broder, "Inhibition of the in vitro infectivityand cytopathic effect of human T-lymphotropic virus typeIII/lymphoadenopathy-associated virus (HTLV-III/LAV) by2',3'-dideoxynucleosides", Proc. Natl. Acad. Sci. USA, vol. 83, pp.1911-1915 (1986). The effect of compounds of formula I on clinicalisolates of other HIV-1 strains was determined by obtaining low-passagedvirus from HIV-infected patients and assaying the effect of theinhibitors in preventing infection of the HIV virus in freshly preparedhuman peripheral blood mononuclear cells (PBMCs).

Insofar as compounds of formula I are able to inhibit the replication ofthe HIV virus in human T-cells and furthermore, may be delivered orallyto mammals, they are of evident clinical utility for the treatment ofHIV infection. These tests are predictive of the compounds ability toinhibit HIV protease in vivo.

EXAMPLE 1

A. Compound XI ((syn)-OH, D'=benzyl)

184 g of Brockman Super I grade neutral alumina was slurried insufficient diethyl ether to form a thick, stirrable suspension and wastreated with 7.48 mL of benzylamine. After stirring for 5 min, 7.28 g of(1S,2S)-1-(N-benzyoxycarbonyl)-amino-2-phenylethyl-oxirane was added andthe mixture stirred for 15 h. The mixture was treated with 15.28 g ofdi-tert-butylpyrocarbonate and 4.70 mL of diisopropylethylamine. Thismixture was stirred for 3.5 h, then treated with 600 mL of methanol,allowed to stand for 3.5 h, and filtered to yield a yellow oil, whichwas purified by silica gel chromatography using a gradient of 0.5 to1.5% methanol in methylene chloride to yield 3.88 g of the desiredproduct as a white solid. Further washing the filter cake with methanoland with 3% ammonium hydroxide in methanol yielded 2.2 g of4-benzylamino-2-N-benzyloxycarbonylamino-3-hydroxy-1-phenylbutane inseveral portions. Each of these portions was treated separately, as asolution in methylene chloride, with 1.1 molar equivalents each ofdi-tert butylpyrocarbonate and diisopropylethylamine, followed byaqueous workup with water, 10% aqueous KHSO₄, and brine, drying overMgSO₄, and concentration in vacuo. The combined products of thesereactions were purified by silica gel chromatography using a gradient of5% to 15% diethyl ether in methylene chloride. The resulting purefractions were collected and combined with the previously purifiedproduct to yield 5.49 g of a white solid. TLC: Rf=0.56, 5% methanol/CH₂Cl₂ ; (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound XII ((syn)-OH, D'=benzyl)

A solution of 5.49 g of the resultant compound of Example 1A in 40 mL ofethanol was hydrogenated under a slight positive pressure of hydrogen inthe presence of 380 mg of 10% palladium on carbon for 16 h. Afterfiltering and concentrating in vacuo, the desired product was obtainedas 4.03 g of a white solid. TLC: Rf=0.21, 95:5:0.5 CH₂ Cl₂/methanol/concentrated NH₄ OH.

C. Compound XIII ((syn)-OH, A=benzyloxycarbonyl, D'=benzyl)

A solution of 3.02 g of the resultant compound of Example 1B in 150 mLof methylene chloride was treated with 4.35 g of N.sup.α -Cbz-N.sup.δ-trityl asparagine, 1.16 g of hydroxybenzotriazole hydrate, and 1.64 gof 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Themixture was stirred for 16 h, then diluted with 3 volumes of diethylether and washed sequentially with water, saturated NaHCO₃ solution, 10%KHSO₄ solution, and brine. After drying over MgSO₄ and concentrating invacuo, a yellow oil was obtained which was purified by chromatography ona Florisil column using a gradient of 0% to 25% EtOAc in CH₂ Cl₂ aseluant to yield 8.00 g of the title compound as a white foam. TLC:Rf=0.51, 5% methanol/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistent withstructure.

D. Compound XIV ((syn)-OH, A=H, D'=benzyl)

A solution of 7.90 g of the resultant compound of Example 1C in 150 mLof ethanol was hydrogenated under a slight positive pressure of hydrogenin the presence of 550 mg of 10% palladium on carbon for 2.5 h, then ca.50 mg more 10% palladium on carbon was added, the mixture was thenfiltered and concentrated in vacuo to give the desired product as 6.66 gof a white solid which was used without subsequent purification. TLC:Rf=0.26, 95:5:0.5 CH₂ Cl₂ /methanol/concentrated NH₄ OH.

E. Compound XIV ((syn)-OH, A=quinoline-2-carbonyl, D'=benzyl)

A suspension of 1.51 g of quinaldic acid and 6.17 g of the resultantcompound of Example 1D in 150 mL of acetonitrile was treated with 1.52mL of diisopropylethylamine and 3.58 g of BOP reagent. The mixture wasstirred for 14 h, then concentrated in vacuo. The gummy residue waspartitioned between ether and water, and the organic layer was washedsequentially with brine, saturated NaHCO₃ solution, water, 10% KHSO₄solution, and brine, then dried over MgSO₄ and concentrated in vacuo.Subsequent purification by silica gel chromatography using 0% to 8.5%solvent A in methylene chloride (where solvent A is defined as 90:10:1,methylene chloride/methanol/concentrated ammonium hydroxide) yielded5.79 g of the title compound as a white foam, along with ca. 600 mg ofslightly impure side fractions. TLC: Rf=0.41, 5% methanol/CH₂ Cl₂ ; (¹H)-NMR (CDCl₃) consistent with structure.

F. Compound 1

A 58 mg portion of the resultant compound of Example 1E was treated with1 mL of 90% aqueous TFA and allowed to stand for 17 h. The mixture wasconcentrated in vacuo and the residue taken up in 3 mL of CH₂ Cl₂,treated with 100 μL of DIEA, and cooled to 0° C. To this solution wasadded 26 μL of benzenesulfonyl chloride, and the mixture was stirred for18 h, warming slowly to ambient temperature. After concentration of themixture in vacuo, the residue was purified by thick layer silica gelchromatography using 5% MeOH/CH₂ Cl₂ as eluant followed by preparativereversed-phase C₁₈ HPLC using a linear gradient of 40% to 100% CH₃ CN/H₂O with 0.1% TFA for elution to obtain 8.3 mg of the title compound. TLC:Rf=0.50, 5% MeOH/CH₂ Cl₂. HPLC: Rt=17.8 min. NMR (DMSO-d₆)δ 2.62 (dd,1H); 2.76 9d, 2H); 2.80 (dd, 1H); 3.11, (d, 2H); 3.34 (dd, 1H); 4.59 (brs, 1H); 4.68 (br s, 1H); 3.97 (m, 1H); 4.20 (d, 1H), 4.35 (d, 1H); 4.68(dd, 1H); 6.39 (d, 1H); 6.74 (t, 1H); 6.81 (t, 2H); 6.93 (d, 2H);7.12-7.24 (m, 6H); 7.51 (t, 2H); 7.57 (t, 1H); 7.62 (dd, 1H); 7.77 (t,2H), 7.96 (d, 1H); 8.09 (d, 1H); 8.16 (d, 1H); 8.31 (d, 1H); 8.53 (d,1H).

EXAMPLE 2

Compound 2

A 150 mg portion of the resultant compound of Example 1E was dissolvedin 1 mL of 90% aqueous TFA and stirred at ambient temperature overnight,then concentrated in vacuo. The crude TFA salt residue was dissolved in7 mL of dry methylene chloride and the pH of the solution was adjustedto pH 8 with 1N NaOH. 56 mg of a mixture of 4-fluoro-3-acetamidobenzenesulfonylchloride and 3-fluoro-4-acetamidobenzene sulfonylchloride (˜1:1)was added and the mixture stirred vigorously for 3 hours after which anadditional 25 mg was added and the reaction allowed to continue for anadditional 12 hours. The reaction was then diluted with 50 mL ofethylene chloride and the organic layer was washed sequentially withwater and brine, dried over MgSO₄ and concentrated in vacuo. The cruderesidue was purified using a silica gel flash chromatography columnusing a gradient of 3% to 5% MeOH in methylene chloride as eluant toyield 60 mg of the title compounds. TLC: Rf=0.50, 10% MeOH/CH₂ Cl₂ ;HPLC: Rt=13.93 min. NMR (CDCl₃): δ9.05 (s, 1H); 8.65 (d, 0.5H); 8.58 (t,0.5H), 8.20 (dd, 0.5H), 7.85 (d, 1H) 7.75 (m, 0.5H), 7.45-7.63 (m,1.5H), 7.14-7.25 (m, 6H), 6.78-6.95 (m, 5H), 6.70 (d, 1H), 6.41 (s,0.5H), 6.25 (s, 0.5H), 6.18 (s, 0.5H), 6.10 (s, 0.5H), 4.88 (m, 0.5H),4.81 (m, 0.5H), 4.37 (d, 1H), 4.35 (m, 1H), 4.21 (d, 1H), 4.00 (m, 1H),3.46 (m, 0.5H), 3.35 (m, 0.5H), 3.27 (d, 0.5H), 3.16 (d, 0.5H), 3.14 (d,1H), 2.45-2,75 (m, 5H); 2.16, 2.20 (2 s, 3H total).

EXAMPLE 3

Compound 3

A 23 mg portion of the resultant compound of Example 1E was treated with1 mL of 90% aqueous TFA and allowed to stand for 15 h. The mixture wasconcentrated in vacuo and the residue taken upon in 2 mL of CH₂ Cl₂,treated with 6 μL of DIEA, and cooled to 0° C. To this solution wasadded 23 mg of 3,5-dimethylisoxazole-4-sulfonyl chloride, and themixture was stirred for 18 h, warming slowly to ambient temperature.After concentration of the mixture in vacuo, the residue was purified bypreparative reversed-phase C₁₈ HPLC using a linear gradient of 35% to100% CH₃ CN/H₂ O with 0.1% TFA for elution to obtain 1.1 mg of the titlecompound. TLC: Rf=0.55, 10% MeOH/CH₂ Cl₂. HPLC: Rt=14.5 min; (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 4

Compound 4

A 33 mg portion of the resultant compound of Example 1E was treated with1 mL of 90% aqueous TFA and allowed to stand for 15 h. The mixture wasconcentrated in vacuo and the residue taken up in 3 mL of CH₂ Cl₂,treated with 16 μL of DIEA, and cooled to 0° C. To this solution wasadded 10 μL of 3-trifluoromethylbenzene sulfonyl chloride, and themixture was stirred for 18 h, warming slowly to ambient temperature.After concentration of the mixture in vacuo, the residue was purified bypreparative reversed-phase C₁₈ HPLC using a linear gradient of 35% to100% CH₃ CN/H₂ O with 0.1% TFA for elution to obtain 1.1 mg of the titlecompound. TLC: Rf=0.55, 10% MeOH/CH₂ Cl₂. HPLC: Rt=14.5 min; (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 5

Compound 5

A 20 mg portion of the resultant compound of Example 1E was treated with1 mL of 90% aqueous TFA and allowed to stand for 18 h. The mixture wasconcentrated in vacuo and the residue taken up in 1 mL of CH₂ Cl₂,treated with 10 μL of DIEA, and cooled to 0° C. To this solution wasadded 13 mg of 2-acetamido-4-methyl-5-thiazolesulfonyl chloride, and themixture was stirred for 17 h, warming slowly to ambient temperature.After concentration of the mixture in vacuo, the residue was purified bypreparative reversed-phase C₁₈ HPLC using a linear gradient of 35% to100% CH₃ CN/H₂ O with 0.1% TFA for elution to obtain 0.40 mg of thetitle compound. TLC: Rf=0.5, 10% MeOH/CH₂ Cl₂. HPLC: Rt=13.8 min; (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 6

Compound 6

A 33 mg portion of the resultant compound of Example 1E was treated with1 mL of 90% aqueous TFA and allowed to stand for 16 h. The mixture wasconcentrated in vacuo and the residue taken up in 2 mL of CH₂ Cl₂,treated with 16 μL of DIEA, and cooled to 0° C. To this solution wasadded 11 mg of 5-(isoxazol-3-yl)thiophene-2-sulfonyl chloride, and themixture was stirred for 18 h, warming slowly to ambient temperature.After concentration of the mixture in vacuo, the residue was purified bypreparative reversed-phase C₁₈ HPLC using a linear gradient of 35% to100% CH₃ CN/H₂ O with 0.1% TFA for elution to obtain 1.5 mg of the titlecompound. TLC: Rf=0.7, 10% MeOH/CH₂ Cl₂. HPLC: Rt=14.7 min; (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 7

Compound 7

A 35.5 mg portion of the resultant compound of Example 1E was treatedwith 1 mL of 90% aqueous TFA and allowed to stand for 18 h. The mixturewas concentrated in vacuo and the residue taken up in 3 mL of CH₂ Cl₂,treated with 16 μL of DIEA, and cooled to 0° C. To this solution wasadded 10 mg of 3-chlorosulfonylbenzoic acid, and the mixture was stirredfor 16 h, warming slowly to ambient temperature. After concentration ofthe mixture in vacuo, the residue was purified by preparativereversed-phase C₁₈ HPLC using a linear gradient of 35% to 100% CH₃ CN/H₂O with 0.1% tTFA for elution to obtain 1.6 mg of the title compound.TLC: Rf=0.7, 10% MeOH/CH₂ Cl₂. HPLC: Rt=13.6 min; (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 8

Compound 8

0.04 mmol of the resultant compound of Example 10A was converted to thefree base by partitioning between EtOAc and sat. NaHCO₃. Treatment ofthe resulting compound with an excess of 1% HCl/MeOH and concentrationin vacuo yielded the hydrochloride salt as a white solid. This compoundwas suspended in CH₂ Cl₂ and treated with sufficient DIEA to bring thepH to >10 (moist pH paper). The solution was treated with 7 molarequivalents of chlorotrimethylsilane and stirred for 15 h undernitrogen, then treated with 0.06 mmol of methane sulfonyl chloride andstirred for 1 h. The resulting mixture was concentrated to a smallvolume, applied directly to a thick layer silica gel plate and elutedwith 7% MeOH/CH₂ Cl₂. The primary UV-quenching band was isolated andfurther purified by preparative reversed-phase HPLC to yield the titlecompound as a white solid. TLC: Rf=0.65, 10% CH₃ OH/CH₂ Cl₂, HPLC:Rt=12.3 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLES 9 AND 192

A. Compound XIV ((syn, anti-OH, A=quinoline-2-carbonyl, D'=isobutyl)

A solution of 317 mg (0.425 mmol) of the resultant compounds of Example17B, diastereomer B and 0.11 mL (0.637 mmol) of diisopropylethyl aminein 7 mL of dichloromethane was treated with 139.1 mg (0.637 mmol) ofdi-tert-butyl dicarbonate. After 24 hours, the mixture was diluted withdichloromethane. The mixture was washed with water, 5% NaHCO₃, 0.5N HCl,brine then dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was purified by low pressure silica gel column chromatographyusing a 20% ethyl acetate/dichloromethane as eluent to yield 81.2 mg ofthe fast moving hydroxyl diastereomer, 65.8 mg of the slower movinghydroxyl diastereomer, and 65.8 mg of the mixed diastereomers. TLC:Rf=0.60, 0.67, 40% EtOAc/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistent withstructure.

B. Compounds 9 and 192

A solution of 35.1 mg (0.041 mmol) of the resultant mixed diastereomers(˜1:1) of Example 9/192A in 0.8 mL of dichloromethane was treated with0.8 mL of trifluoroacetic acid. After 4 hours, the mixture wasconcentrated in vacuo. TLC: Rf=0.11, 10% CH₃ OH/CH₂ Cl₂. To a solutionof the resulting trifluoroacetic acid salt (entire yield) in 1 mL ofdichloromethane was sequentialled added 0.3 mL of saturated NaHCO₃, asmall amount of solid NaHCO₃ and 11.8 mg (0.054 mmol) ofbenzofurazan-4-sulphonyl chloride. After 3 hours, the mixture wasdiluted with dichloromethane. The two layers were separated and theaqueous layer was extracted once with dichloromethane. The combinedorganic layer was washed with brine then dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by preparative HPLC toyield 2.0 mg of compound 9 as a white solid: TLC: Rf=0.20, 5% CH₃ OH/CH₂Cl₂ ; HPLC, RT 14.2 min. 2.7 mg of compound 192 was also obtained as awhite solid, which was determined by NMR and HPLC to be contaminatedwith ˜25% of compound 9: TLC: Rf=0.20, 5% CH₃ OH/CH₂ Cl₂ ; HPLC, Rt=14.2min. (¹ H)-NMR consistent with structure.

EXAMPLE 10

A. Compound XV ((syn)-OH, A=quinoline-2-carbonyl, D'=benzyl; TFA salt)

A 0° C. solution of 1.027 g portion of the resultant compound of Example1E in 5 mL of CH₂ Cl₂ was treated with 5 mL of TFA and allowed to standfor 3 h. The mixture was concentrated in vacuo to yield 0.95 g of thetitle compound, which was used without subsequent purification.

B. Compound 10

A solution of 30.2 mg of the resultant compound of Example 10A in 3 mLof CH₂ Cl₂ was treated with 0.33 mL of DIEA and 31.1 mg ofm-benzenedisulfonyl chloride. The mixture was stirred for 2 h, thentreated with 2 mL of concentrated aqueous ammonium hydroxide. Thebiphasic mixture was stirred for an additional 16 h, concentrated invacuo, and the residue partitioned between ethyl acetate and brine. Theorganic layer was dried over anhydrous MgSO₄ and concentrated in vacuo,and the residue was purified by preparative thick layer silica gelchromatography using 3% MeOH/CH₂ Cl₂ as eluant to yield 4.5 mg of thetitle compound. TLC: Rf=0.5, 3% MeOH/CH₂ Cl₂ as eluant to yield 4.5 mgof the title compound. TLC: Rf=0.5, 3% MeOH/CH₂ Cl₂. HPLC: Rt=13.4 min;(¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 11

Compound 11

A solution of 57.9 mg of the resultant compound of Example 10A in 5 mLof CH₂ Cl₂ was treated with 30 μL of DIEA and 9.3 μL ofdimethylsulfamoyl chloride. The mixture was stirred for 12 h, thentreated with an additional 30 μL of DIEA and 9.3 μL of dimethylsulfamoylchloride and the reaction was allowed to proceed an additional 12 hours.The mixture was then diluted with CH₂ Cl₂ and washed with saturated NH₄Cl; the aqueous layer was washed with CH₂ Cl₂, and the combined organicextracts were dried over MgSO₄. Filtration and concentration provided aresidue which was chromatographed on a silica gel column using 2.5%MeOH/EtOAc as eluent, yielding a slightly impure product which wasfurther purified by preparative HPLC using a linear gradient of 35% to100% CH₃ /CN/H₂ O with 0.1% TFA for elution. HPLC: Rt=13.0 minutes. NMR(CDCL₃): δ9.15 (d, 1H), 8.34 (d, 1H), 8.22 (d, 1H), 8.18 (d, 1H), 7.90(d, 1H), 7.80 (t, 1H), 7.65 (t, 1H), 7.16-738 (m, 5H), 7.05 (d, 1H),6.95 (t, 1H), 6.87 (t, 1H), 5.85 (br s, 1H), 5.62 (br s, 1H), 4.87 (M,1H), 4.46 (s, 2H), 4.08 (m, 1H), 3.66 (m, 1H), 3.30 (m, 2H), 2.59-2.94(m, 4H), 2.81 (s, 6H).

EXAMPLE 12

A. Compound XIV ((syn)-OH, A=quinoline-2-carbonyl, D'=benzyl;trifluoroacetate salt)

To a solution of 1.027 g (1.164 mmol) of the resultant compound ofExample 1E in CH₂ Cl₂ (5 mL) at 0° to 5° C. was addedtrifluoromethanesulfonic acid (5 mL). After stirring for 3 h, thereaction mixture was concentrated in vacuo to provide 0.95 g of lightyellow, gummy product, containing one equivalent of triphenylmethanol,which was used without subsequent purification.

B. Compound 12

To a solution of 30.2 mg (0.038 mmol) of the resultant compound ofExample 12A in CH₂ Cl₂ (3 mL) was added diisopropylethylamine (0.33 mL,0.189 mmol), and 2-(pyrid-2-yl)-tyiophene-5-sulfonyl chloride 13 mg,(0.249 mmol). After 14 h, the resulting mixture was diluted with ethylacetate, washed with saturated brine, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified bypreparative reversed-phase chromatography using a 5% to 100% H₂O/acetonitrile gradient as eluant to yield the title product.

EXAMPLE 13

Compound 13

To a solution of 30 mg (0.038 mmol) of the resultant compound of Example12A in CH₂ Cl₂ (3 mL) was added diisopropylethylamine (0.33 mL, 0.189mmol), and 2-(3-phenylsulfonyl)thiophene sulfonyl chloride (0.113 mmol).After stirring for 2 h, the reaction mixture was made biphasic byaddition of 30% ammonium hydroxide solution (2 mL). After stirring foran additional 16 h, the resultant mixture was concentrated in vacuo,reconstituted in ethyl acetate, washed with saturated brine, dried overmagnesium sulfate, filtered, and re-concentrated in vacuo. Purificationby thin layer preparative chromatography yielded the desired compound.

EXAMPLE 14

Compound 14

The resulting compound of Example 17B, diastereomer B (170 mg) wastreated with 1 mL of 90% aqueous TFA and allowed to stand for 12 h. Themixture was concentrated in vacuo and the residue taken up in 5 mL ofdry CH₂ Cl₂. To this solution, 3 mL of saturated aqueous sodiumbicarbonate and 50 mg of 4-fluorobenzenesulfonyl chloride was added andthe mixture stirred for 3 h. The resulting mixture was diluted with CH₂Cl₂ and washed with water, dried over magnesium sulfate and filtered.After concentration of the mixture in vacuo, a portion of the residuewas purified by preparative reversed-phase C₁₈ HPLC using a lineargradient of 35% to 100% CH₃ CN/H₂ O with 0.1% TFA for elution to obtain3.0 mg of the title compound. TLC: Rf=0.25, 5% CH₃ OH in CH₂ Cl₂. HPLC:Rt=14.78 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 15

Compound 15

A sample of a mixture of 4-fluoro-3-acetamidobenzenesulfonyl chlorideand 3-fluoro-4-acetamidobenzenesulfonyl chloride (approx. 1:1; obtainedfrom Maybridge Chemicals) was resolved into its respective regioisomersby silica gel chromatography using 10% isopropyl alcohol/hexane aseluent. A solution of 4-acetamido-3-fluorobenzenesulfonyl chloride (30mg) and the resulting compound of Example 17B, diastereomer B (80 mg) in10 mL of CH₂ Cl₂ was reacted in the same manner as described for Example14. After workup and purification of a portion of the product bypreparative reversed-phase C₁₈ HPLC using a linear gradient of 35% to100% CH₃ CN/H₂ O with 0.1% TFA as eluent, 1.2 mg of the title compoundwas obtained as a white solid. TLC: Rf=0.25, 5% CH₃ OH in CH₂ Cl₂. HPLC:Rt=12.91 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 16

Compound 16

80 mg of the resulting compound of Example 17B, diastereomer B, wasreacted with 45 mg of 3-acetamido-4-fluorobenzenesulfonyl chloride inthe same manner as described for Example 14. After workup andpurification of a portion of the product by preparative reversed-phaseC₁₈ HPLC using a linear gradient of 35 to 100% CH₃ CN/H₂ O with 0.1% TFAas eluent, 1.4 mg of the title compound was obtained. TLC: Rf=0.25, 5%CH₃ OH in CH₂ Cl₂. HPLC: Rt=12.91 min; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 17

A. (2S)-2-((1S, 2R syn,anti)-3-(2-methylpropyl)amino-1-benzyl-2-hydoxypropyl)-N¹-((quinoline-2-carbonyl)-amino)-N⁴ -trityl succinamide

A solution of 683.1 mg (0.96 mmol) of the resultant compounds of Example191D and 1.9 mL (19.2 mmol) of isobutylamine in 10 mL of acetonitrile ina sealed tube was heated at 90°-100° C. for 24 hours. After cooling toroom temperature, the mixture was concentrated in vacuo. The residue wastaken up in dichloromethane and washed with water, brine, then driedover MgSO₄, filtered and concentrated in vacuo to yield 783.8 mg of themixed diastereomeric products. TLC: Rf=0.11, 10% CH₃ OH/CH₂ Cl₂ ; (¹H)-NMR (CDCl₃) consistent with structure.

B. Compound XIII, ((syn, anti)-OH, P=quinoline-2-carbonyl, D'=isobutyl)

A solution of 583.8 mg of the resultant compounds of Example 17A and 0.2mL of diisopropylethylamine in 10 mL of dichloromethane was treated with256 mg of di-tert-butyl dicarbonate. After 24 hours, the mixture wasdiluted with dichloromethane. The mixture was washed with water, 5%NaHCO3, 0.5N HCl, brine then dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by low pressure silica gel columnchromatography using a 20% ethyl acetate/dichloromethane as eluent toyield 154.6 mg of the fast moving diastereomer A, later identified ashaving the anti configuration at the hydroxyl center; 98.8 mg of theslower moving diastereomer B, having the syn configuration at thehydroxyl center, and 204.6 mg of the mixed diastereomers A and B. TLC:Rf=0.60, 0.67, 40% EtOAc/CH₂ Cl₂.

C. Compound 17

A solution of 64.6 mg of the resultant compounds of Example 17B,diastereomer B, in 1.5 mL of dichloromethane was treated with 1.5 mL oftrifluoroacetic acid. After 4 hours, the mixture was concentrated invacuo to yield the amine trifluoroacetate salt. TLC: Rf=0.11, 10% CH₃OH/CH₂ Cl₂. To a solution of 17.8 mg of the resultant trifluoroacetatesalt in 1 mL of dichloromethane was sequentially added 0.3 mL ofsaturated NaHCO₃, a small amount of solid NaHCO₃ and 10.7 mg of4-acetamidobenzenesulphonyl chloride. After 3 hours, the mixture wasdiluted with dichloromethane. The two layers were separated and theaqueous layer was extracted once with dichloromethane. The combinedorganic layer was washed with brine then dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by preparative HPLC toyield 14.4 mg of the title compound as a white solid; TLC: Rf=0.54, 10%CH₃ OH/CH₂ Cl₂ ; HPLC, Rt=13.58 min; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 18

Compound 18

To a solution of 20.8 mg (0.041 mmol) of the crude trifluoroacetate saltobtained as from Example 17B, diastereomer B, in 1 mL of dichloromethanewas sequentially added 0.3 mL of saturated NaHCO₃, a small amount ofsolid NaHCO₃ and 13.6 mg (0.054 mmol) of2-acetamido-4-methyl-5-thiazolesulphonyl chloride. After 3 hours, themixture was diluted with dichloromethane. The two layers were separatedand the aqueous layer was extracted once with dichloromethane. Thecombined organic layer was washed with brine then dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified bypreparative HPLC to yield 4.8 mg of the title compound as a white solid;TLC: Rf=0.50, 10% CH₃ OH/CH₂ Cl₂ ; HPLC: Rt=13.35 min; (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 19

A. Sodium 3-acetamidobenzenesulfonate

A solution of 118.6 mg (0.55 mmol) of 3-acetamidobenzenesulfonic acid in0.5 mL of water was treated with 0.55 mL (0.55 mmol) of 1.0N NaOH at 0°C. After stirring at room temperature for 4 hours, the mixture wasconcentrated to dryness and used without subsequent purification.

B. 3-Acetamidobenzenesulfonyl chloride

The crude mixture from Example 19A was cooled to 0° C. and 0.29 g (1.38mmol) of phosphorus pentachloride was added. The mixture of solid wasstirred for 3 hours then 5 mL dichloromethane was added. After 24 hours,the slurry was filtered and concentrated in vacuo to yield 81.4 mg ofsolid product which was used without subsequent purification. TLC:Rf=0.50, 40% EtOAC/CH₂ Cl₂.

C. Compound 19

A solution of 82.7 mg (0.098 mmol) of diastereomer B, obtained inExample 17B, in 2 mL of dichloromethane was treated with 2 mL oftrifluoroacetic acid. After 4 hours, the mixture was concentrated invacuo to yield the amine trifluoroacetate salt which was used withoutfurther purification; TLC: Rf=0.11, 10% CH₃ OH/CH₂ Cl₂. A solution ofthis salt (entire yield) in 2 mL of dichloromethane was treatedsequentially with 0.5 mL of saturated NaHCHO₃, small amount of solidNaHCO₃ and a solution of 81.4 mg (0.046 mmol) of the resultant compoundof Example 19B. After 3 hours, the mixture was diluted withdichloromethane. The two layers were separated and the aqueous layer wasextracted once with dichloromethane. The combined organic layer waswashed with brine then dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by preparative HPLC to yield 24.7 mg ofthe title compound as a white solid; TLC: Rf=0.42, 10% CH₃ OH/CH₂ Cl₂ ;HPLC: Rt=13.8 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 20

Compound 20

A solution of 209.0 mg (0.24 mmol) of the resultant compound of Example17B, diastereomer B, in 5 mL of dichloromethane was treated with 5 mL oftrifluoroacetic acid. After 4 hours, the mixture was concentrated invacuo. TLC: Rf=0.11, 10% CH₃ OH/CH₂ Cl₂. To a solution of this residuein 2 mL of dichloromethane was sequentially added 0.5 mL of saturatedNaHCO₃, a small amount of solid NaHCO₃ and 70.2 mg (0.32 mmol) ofbenzofurazan-4-sulphonyl chloride. After 3 hours, the mixture wasdiluted with dichloromethane. The two layers were separated and theaqueous layer was extracted once with dichloromethane. The combinedorganic layer was washed with brine then dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by preparative HPLC toyield 108.0 mg of the title compound as a white solid; TLC: Rf=0.60, 10%CH₃ OH/CH₂ Cl₂ ; HPLC: Rt=14.95 min; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 21

Compound 21

The resulting compound of Example 17B, diastereomer B, (228 mg, 0.27mmol) was dissolved in 1:1 CH₂ Cl₂ /TFA (10 mL), and the reactionmixture stirred for 3.5 hours, then concentrated to dryness to affordthe product trifluoroacetate salt as a yellow solid which was used inthe next reaction without purification. To a solution of this residue(34.7 mg, 0.05 mmol) in CH₂ Cl₂ (3 mL) was added Heunig's base (41 μl,0.24 mmol) and dimethylsulfamoyl chloride (11 μl, 0.09 mmol), and thereaction was stirred for 17 hours at room temperature. The reactionmixture was then diluted with CH₂ Cl₂ and washed with saturated NH₄ Cl,and the organic layer was dried over MgSO₄. Filtration and concentrationprovided a residue which was chromatographed on a silica gel columnusing 8% CH₃ OH/CH₂ Cl₂ as eluent, yielding the desired compound whichwas further subject to purification by preparative HPLC. HPLC: Rt=13.8minutes. TLC: Rf=0.40, 8% CH₃ OH/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 22

A. N.sup.α -isocyano-L-valine methyl ester

To the HCl salt of valine methyl ester (2.08 g, 12.40 mmol) in toluene(20 mL) was added a 20% solution of phosgene in toluene (32 mL, 62.00mmol), and the solution was heated at reflux for 12 hours. The reactionwas then cooled to room temperature and concentrated in vacuo to give apale yellow liquid which was used in the subsequent reaction withoutpurification. TLC: Rf=0.88, 50% Hexane/EtOAc; (¹ H)-NMR (CDCl₃)consistent with structure.

B. N.sup.α -(2-pyridylmethyl)-oxycarbonyl-L-valine methyl ester

A mixture of 2-pyridylcarbinol (941 μl, 9.75 mmol) and the resultingcompound of Example 22A (1.28 g, 8.12 mmol) were allowed to stir in CH₂Cl₂ (7 mL) for 12 hours, then the reaction was concentrated and theresidue chromatographed with 50% hexane/EtOAc to afford 2.03 grams ofthe title compound as a colorless oil. TLC: Rf=0.26, 50% Hexane/EtOAc;(¹ H)-NMR (CDCl₃) consistent with structure.

C. N.sup.α -(2-pyridylmethyl)-oxycarbonyl-L-valine

A solution of the resulting compound of Example 22B (634 mg, 2.38 mmol)in a 1/1 mixture of 1N HCl/THF (6 mL) containing 12N HCl (0.5 mL) wasallowed to stir at room temperature over 15 hours, but much startingmaterial was still present by TLC. Hence, more 12N HCL was added (1 mL),and the reaction stirred an additional 48 hours. The reaction was thenconcentrated to dryness and diluted with CH₂ Cl₂, yielding the desiredcarboxylic acid as an insoluble resin which was washed with additionalCH₂ Cl₂, providing 22C which contained minor quantities of 22B. Thismaterial was used in the subsequent reaction without furtherpurification. TLC: Rf=0.11, 8% CH₃ OH/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃)consistent with structure.

D. Compound XXX (P=(2-pyridylmethyl)-oxycarbonyl, R³ =isopropyl, R^(3')=H, D'=isobutyl, P'=tert-butoxycarbonyl)

To the resulting compound of Example 21B (277 mg, 0.82 mmol) in CH₂ Cl₂(5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (210 mg, 1.10 mmol), the acid 22C (402 mg, 1.10 mmol), and1-hydroxybenzotriazole hydrate (148 mg, 1.10 mmol). The reactionproceeded for 12 hours at room temperature, then was diluted with CH₂Cl₂ and washed successively with saturated NH₄ Cl and NaHCO₃, and theorganic layer was dried over MgSO₄. Filtration and concentrationprovided a residue which was chromatographed on a silica gel columnusing 17% THF/CH₂ Cl₂ as eluent, yielding 396 mg of product. TLC:Rf=0.26, 17% THF/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistent with structure.

E. Compound 22

The resulting compound of Example 22D (396 mg, 0.69 mmol) was dissolvedin 90% aqueous TFA (11 mL), and the reaction mixture stirred for 3 hoursat room temperature, then was concentrated to dryness. To a solution ofthis residue (231 mg. 0.33 mmol) in CH₂ Cl₂ (5 mL) was added excesssolid NaHCO₃ (approx. 1 gram) and saturated aqueous NaHCO₃ (20 μl),followed by N-acetylsulfanilyl chloride (116 mg, 0.50 mmol), and thereaction proceeded for 12 hours at room temperature. The reactionmixture was then diluted with CH₂ Cl₂ and washed with saturated NaHCO₃,and the organic layer was dried over MgSO₄. Filtration and concentrationprovided a residue which was chromatographed on a silica gel columnusing 8% CH₃ OH/CH₂ Cl₂ as eluent, yielding the desired compound whichwas further subject to purification by preparative HPLC (76.1 mg of 3was obtained). HPLC: Rt=12.1 minutes. TLC: Rf=0.46, 8% CH₃ OH/CH₂ Cl₂ ;NMR (CDCl₃): 8.76 (d, 1H), 8.40 (br s, 1H), 8.26 (t, 1H), 7.72 (d, 2H),7.67 (d, 2H), 7.58 (d, 2H), 7.37 (d, 1H), 7.25 (m, 4H), 7.16 (br d, 1H),6.47 (d, 1H), 5.65 (d, 1H), 5.26 (d, 1H), 4.32 (m, 1H), 3.91 (t, 1H),3.83 (m, 1H), 3.23 (d, 1H), 3.05 (m, 2H), 2.68-3.10 (m, 3H), 2.22 (m,3H), 2.0 (m, 1H), 1.82 (m, 1H), 0.85 (d, 3H), 0.80 (d, 3H), 0.71 (d,3H),0.65 (d, 3H).

EXAMPLE 23

Compound 23

Prepared by the same route as described for Example 22, except4-pyridylcarbinol was utilized for reaction with the product of Example22A. HPLC: Rt=12.0 minutes. TLC: Rf=0.50 (8% CH₃ OH/CH₂ Cl₂); (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 24

Compound 24

A solution of the resulting compound of the trifluoroacetic aciddeprotection of Example 22D (as described in Example 22E; 215 mg, 0.31mmol) in CH₂ Cl₂ at room temperature was treated withdiisopropylethylamine (214 μl, 1.23 mmol) and dimethylsulfamoyl chloride(40 μl, 0.37 mmol) in CH₂ Cl₂ at room temperature in CH₂ Cl₂ at roomtemperature for 12 hours. The reaction mixture was concentrated andchromatographed on a silica gel column with 5% CH₃ OH/CH₂ Cl₂ as eluent,yielding the desired compound which was further subject to purificationby preparative HPLC (9.5 mg obtained). HPLC: Rt=14.4 minutes. TLC:Rf=0.88, 11% CH₃ OH/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 25

Compound 25

This compound was prepared by the route described for Example 22, exceptthat 3-pyridylcarbinol was utilized for reaction with the compoundproduced in Example 22A, and in the reaction corresponding to 22E, thetrifluoracetate-deprotected material was reacted withbenzofurazan-4-sulphonyl chloride. HPLC: Rt=9.4 minutes. TLC: Rf=0.10,11% CH₃ OH/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 26

Compound 26

A solution of the resulting compound from the trifluoroacetic aciddeprotection of Example 22D (as described in Example 22E; 27 mg, 0.14mmol) in CH₂ Cl₂ was treated with excess solid NaHCO₃ (approx. 1 gram)and saturated aqueous NaHCO₃ (7 μl), then stirred vigorously at roomtemperature for 3 hours. The reaction mixture was decanted from thesolids, concentrated, then the residue was purified directly bypreparation HPLC (3.0 mg of white solid obtained). HPLC: Rt=14.7minutes; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 27

Compound 27

A solution of 33 mg of the resultant compound of Example 40A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 20 mg of N,N-diisopropylethylamine and 9.3 mg of allylchloroformate. The mixture was stirred for 3 h and then concentrated invacuo. The residue was taken up in ethyl acetate and washed with 0.5NHCl and saturated NaCl then dried over MgSO₄, filtered, and concentratedin vacuo. The residue was purified by preparative thin layer silica gelchromatography using a 2:1 mixture of (5:10:85 NH₄ OH/CH₃ OH/CH₂Cl₂):diethyl ether to yield 24 mg of the title compound as a whitesolid. TLC: Rf=0.53, 5:10:85 NH₄ OH/CH₃ OH/CH₂ Cl₂. HPLC: Rt=14.53 min;(¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 28

Compound 28

A solution of 47.5 mg of the resultant compound of Example 40A in CH₂Cl₂ was treated sequentially, at ambient temperature under an atmosphereof nitrogen, with 28.7 mg of N,N-diisopropylethylamine and 15.2 mg ofisobutyl chloroformate. The mixture was stirred 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by preparative thinlayer silica gel chromatography using a 2:1 mixture of (5:10:85 NH₄OH/CH₃ OH/CH₂ Cl₂):diethyl ether to yield 45 mg of the title compound asa white solid. TLC: Rf=0.60, 5:10:85 NH₄ OH/CH₃ OH/CH₂ Cl₂. HPLC:Rt=15.58 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 29

Compound 29

A solution of 35.6 mg of the resultant compound of Example 40A in CH₂Cl₂ was treated sequentially, at ambient temperature under an atmosphereof nitrogen, with 21.5 mg of N,N-diisopropylethylamine and 0.083 nL of1.0M isopropyl chloroformate. The mixture was stirred 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by preparative thinlayer silica gel chromatography using a 2:1 mixture of 5:10:85 NH₄OH/CH₃ OH/CH₂ Cl₂ :diethyl ether to yield 33.2 mg of the title compoundas a white solid. TLC: Rf=0.56, 5:10:85 NH₄ OH/CH₃ OH/CH₂ Cl₂. HPLC:Rt=14.81 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 30

A. (2-Pyrrolidinonyl-hydroxyethyl-N-hydroxysuccinimdyl carbonate

A solution of 572 mg of 1-(2-hydroxyethyl)-2-pyrrolidinone and 1.70 g ofN,N'-disuccinimidyl carbonate in acetonitrile was treated, at ambienttemperature under an atmosphere of nitrogen, with 1717 mg ofN,N-diisopropylethylamine. The mixture was stirred for 14 h andconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with saturated NaHCO₃, saturated NaCl, then dried over MgSO₄,filtered, and concentrated in vacuo to yield 200 mg of a white solid.TLC: Rf=0.56, 10% isopropanol in CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistentwith structure.

B. Compound 30

A solution of 68 mg of the resultant compound of Example 30A in CH₂ Cl₂was added, at ambient temperature under an atmosphere of nitrogen, to asolution of 32 mg of the resultant compound of Example 40A and 39 mgN,N-diisopropylethylamine in CH₂ Cl₂. The mixture was stirred for 4 h,diluted with CH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl,then dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas subjected to preparative thin layer silica gel chromatography usinga 2:1 mixture of 5:10:85 NH₄ OH/CH₃ OH/CH₂ Cl₂ :diethyl ether to yield45 mg of residue. About 20 mg of this residue was purified bypreparative HPLC to yield 13.5 mg of the title compound as a whitesolid. TLC: Rf=0.47, 5:10:85 NH₄ OH/CH₃ OH/CH₂ Cl₂. HPLC: Rt=12.79 mid;(¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 31

Compound 31

A solution of 39.7 mg of the resultant compound of Example 40A in CH₂Cl₂ was treated sequentially, at ambient temperature under an atmosphereof nitrogen, with 24 mg of N,N-diisopropylethylamine and 14.5 mg ofphenyl chloroformate. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by preparative thinlayer silica gel chromatography using a 2:1 mixture of 5:10:85 NH₄OH/CH₃ OH/CH₂ Cl₂ :diethyl ether to yield 39.7 mg of the title compound.TLC: Rf=0.53, 5:10:85 NH₄ OH/CH₃ OH/CH₂ Cl₂. HPLC: Rt=15.22 min; (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 32

Compound 32

A solution of 391 mg of the resultant compound of Example 39A in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 271 mg of4-fluorobenzenesulfonyl chloride and 117 mg of sodium bicarbonate. Themixture was stirred for 14 h, diluted with CH₂ Cl₂, washed withsaturated NaCl then dried over MgSO₄, filtered, and concentrated invacuo. The residue was purified by low pressure silica gelchromatography using 5% diethyl ether in CH₂ Cl₂ as eluent to yield 420mg of the title compound as a white solid. TLC: Rf=0.20, 5% diethylether in CH₂ Cl₂. HPLC: Rt=17.41 min; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 33

Compound 33

A solution of 30 mg of the resultant compound of Example 40A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 18.1 mg of N,N-diisopropylethylamine and 9.3 mg of benzylisocyanate. The mixture was stirred 14 h and then concetrated in vacuo.The residue was taken up in ethyl acetate and washed with 0.5N HCl andsaturated NaCl then dried over MgSO₄, filtered, and concentrated invacuo. The residue was purified by preparative thin layer silica gelchromatography using a mixture of 5:10:85 NH₄ OH/CH₃ OH/CH₂ Cl₂ to yield30.2 mg of the title compound as a white solid. TLC: Rf=0.56, 5:10:85NH₄ OH/CH₃ OH/CH₂ Cl₂. HPLC: Rt=14.36 min; (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 34

Compound 34

A solution of 55 mg of the resultant compound of Example 40A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 33.3 mg of N,N-diisopropylethylamine and 17.8 mg of2-methoxyethyl chloroformate. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by preparative thinlayer silica gel chromatography using a 2:1 mixture of (5:10:85 NH₄OH/CH₃ OH/CH₂ Cl₂):diethyl ether to yield 48.1 mg of the title compoundas a white solid. TLC: Rf=0.56, 5:10:85 NH₄ OH/CH₃ OH/CH₂ Cl₂. HPLC:Rt=13.43 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 35

A. Compound XXI (D'=isobutyl, A'=4-fluorophenyl, hydrochloride salt)

A solution of 398 mg of the resultant compound of Example 32 in ethylacetate was treated at -20° C. with HCl gas. The HCl was bubbled throughthe mixture for 20 min over which time the temperature was allowed towarm to 20° C. Nitrogen was then bubbled through the mixture for 15 minand solvent removed in vacuo to yield 347 mg of the title compound as awhite solid. TLC: Rf=0.82, 5:10:85 NH₄ OH/CH₃ OH/CH₂ Cl₂ ; (¹ H)-NMR(CDCl₃) consistent with structure. ps B. Compound 35

A solution of 111 mg of the resultant compound of Example 35A in CH₂ Cl₂was added, at ambient temperature under an atmosphere of nitrogen, to asolution of 118 mg of the resultant compound of Example 48A and 133 mgN,N-diisopropylethylamine in CH₂ Cl₂. The mixture was stirred for 14 h,diluted with CH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl,then dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas subjected to preparative thin layer silica gel chromatography using5% CH₃ OH in CH₂ Cl₂ to yield 98.8 mg of the title compound as a whitesolid. TLC: Rf=0.48, 5% CH₃ OH in CH₂ Cl₂. HPLC: Rt=15.18 min; (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 36

Compound 36

A solution of 48 mg of the resultant compound of Example 40A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 29.0 mg of N,N-diisopropylethylamine and 15.1 mg of3-butenyl chloroformate. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by preparative thinlayer silica gel chromatography using a 2:1 mixture of (5:10:85 NH₄OH/CH₃ OH/CH₂ Cl₂):diethyl ether to yield 43.8 mg of the title compoundas a white solid. TLC: Rf=0.83, 5:10:85 NH₄ OH/CH₃ OH/CH₂ Cl₂ ; Rf=0.24,5% diethyl ether in CH₂ Cl₂. HPLC: Rt=14.76 min; (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 37

Compound 37

A solution of 99 mg of the resultant compound of Example 51D in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 83.2 mg of3,4-dichlorobenzenesulfonyl chloride and 29 mg of sodium bicarbonate.The mixture was stirred for 14 h, diluted with CH₂ Cl₂, washed withsaturated NaCl then dried over MgSO₄, filtered, and concentrated invacuo. The residue was subjected to operative thin layer silica gelchromatography using 5% CH₃ OH in CH₂ Cl₂ to yield 107 mg of the titlecompound as a white solid. TLC: Rf=0.35 (5% CH₃ OH in CH₂ Cl₂). HPLC:Rt=17.27 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 38

Compound 38

To a solution of 32 mg of the resultant compound of Example 35A in CH₂Cl₂ was added, at ambient temperature under an atmosphere of nitrogen,14 mg of benzyl chloroformate and 21 mg N,N-diisopropylethylamine. Themixture was stirred for 4 h, diluted with CH₂ Cl₂, washed with saturatedNaHCO₃ and saturated NaCl, then dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by preparative thinlayer silica gel chromatography using 10% diethyl ether in CH₂ Cl₂ aseluent to yield 33 mg of product. TLC: Rf=0.62, 10% diethyl ether in CH₂Cl₂. HPLC: Rt=17.27 min. (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 39

A. Compound XXI (D'=isobutyl, P=tert-butoxy carbonyl, P'=H)

A solution of 4.1 g of epoxide XX (P=Boc) in 30 mL of ethanol wastreated with 22.4 mL of isobutylamine and heated under reflux for 1 h.The mixture was concentrated to yield the title compound as a whitesolid which was used without subsequent purification. NMR (CDCl₃): δ0.91(d, 3H); 0.93 (d, 3H); 1.37 (s, 9H); 1.68 (br s, 2H); 2.40 (d, 2H); 2.68(d, 2H); 2.87 (dd, 1H); 2.99 (dd, 1H); 3.46 (dd, 1H); 3.75 (br s, 1H);3.80 (br s, 1H); 4.69 (d, 1H); 7.19-7.32 (m, 4H).

B. Compound 39

To a solution of 514.1 mg of the resultant compound of Example 39A indichloromethane (10 mL) was added aqueous sodium bicarbonate (5 mL) andN-acetylsulfanilyl chloride (428.4 mg). After 14 h, the resultingmixture was diluted with ethyl acetate, washed with sodium bicarbonate,saturated brine, dried over magnesium sulfate, filtered and concentratedin vacuo. The residue was purified by low pressure silica gel columnchromatography using 20% ethyl acetate in dichloromethane eluent toyield 714.4 mg of the title product. TLC: Rf=0.63, 60% ethylacetate/dichloromethane, HPLC: Rt=15.3 min; (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 40

A. Compound XXII (D'=isobutyl, P=H, E=4-acetamidophenyl), hydrochloridesalt

To a solution of 691.4 mg (1.296 mmol) of the resultant compound ofExample 39B in ethyl acetate (20 mL) at -20° C. was bubbled anhydrousHCl gas for 10 min. The ice bath was removed and after an additional 15min., the reaction mixture was sparged with nitrogen then concentratedin vacuo to provide 610 mg of title product which was used withoutsubsequent purification.

B. Compound 40

A solution of 41.5 mg of the resultant crude compound of Example 40A in5 mL of dichloromethane was treated sequentially, at ambient temperatureunder an atmosphere of nitrogen, with 18.1 mg of L-dihydroorotic acid,0.031 mL (0.176 mmol) diisopropylethylamine, 15.5 mg (0.115 mmol) of1-hydroxybenzotriazole hydrate, 22 mg (0.115 mmol) EDC. After 1 h, theslurry was treated with 1 mL of dimethylformamide. The mixture wasstirred for 16 h and then concentrated in vacuo. The residue was takenup in ethyl acetate and washed with water and saturated brine, driedover magnesium sulfate, filtered and concentrated in vacuo. The residuewas purified by thin layer preparative chromatography using (1/2/17v/v/v/ 30% ammonium hydroxide/methanol/dichlomethane) eluent to provide34.2 mg of the title product. TLC: Rf=0.33, 1/2/17 v/v/v/ 30% ammoniumhydroxide/methanol/dichlomethane). HPLC: Rt=11.3 min; (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 41

Compound 41

To a solution of 42.8 mg of the resultant compound of Example 40A in 5mL dichloromethane was added sequentially, at ambient temperature underan atmosphere of nitrogen, 17.2 mg of N-tert-butyl glyoxalic acid, 0.032mL diisopropylethylamine, 16 mg of 1-hydroxybenzotriazole hydrate, 22.6mg EDC. The mixture was stirred for 16 h and then concentrated in vacuo.The residue was taken up in ethyl acetate and washed with water, 0.5Nhydrochloric acid, washed with sodium bicarbonate, saturated brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by thin layer preparative chromatography using 40%ethyl acetate/dichloromethane eluent to provide 14.9 mg of the titleproduct. TLC: Rf=0.47, 40% ethyl acetate/dichloromethane, HPLC: Rt=15.2min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 41

Compound 42

To a solution of 43.5 mg of the resultant crude compound of Example 40Ain 5 mL dichloromethane was added sequentially at ambient temperature,under an atmosphere of nitrogen, 13.0 mg of succinamic acid, 0.024 mLdiisopropylethylamine, 15.0 mg of 1-hydroxybenzotriazole hydrate, and21.3 mg EDC. The mixture was stirred for 16 h and then concentrated invacuo. The residue was taken up in ethyl acetate and washed with sodiumbicarbonate, saturated brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by thin layerpreparative chromatography using (1/2/11 v/v/v/ 30% ammoniumhydroxide/methanol/dichlomethane) eluent to provide 35.3 mg of the titleproduct. TLC: Rf=0.25, 1/2/11 v/v/v/ 30% ammoniumhydroxide/methanol/dichlomethane, HPLC: Rt=11.6 min; (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 43

Compound 43

To a solution of 42.8 mg of the resultant compound of Example 40A in 5mL dichloromethane was added sequentially, at ambient temperature underan atmosphere of nitrogen, with 14.1 mg of L-pyroglutamic acid, 0.024 mLdiisopropylethylamine, 14.8 mg of 1-hydroxybenzotriazole hydrate, 20.9mg EDC. The mixture was stirred for 16 h and then concentrated in vacuo.The residue was taken up in ethyl acetate and washed with water, 0.5Nhydrochloric acid, washed with sodium bicarbonate, saturated brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by thin layer preparative chromatography using(1/2/11 v/v/v/ 30% ammonium hydroxide/methanol/dichlomethane) eluent toprovide 29.9 mg of the title product. TLC: Rf=0.33, 1/2/11 v/v/v/ 30%ammonium hydroxide/methanol/dichlomethane, HPLC: Rt=11.7 min; (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 44

A. 3-Pyridylmethyl-N-hydroxysucchinimdyl carbonate

To a solution of 181.0 mg of 3 pyidinecarbinol in 5 mL acetonitrile wasadded sequentially at ambient temperature under an atmosphere ofnitrogen, with 0.72 mL diisopropylethylamine and 354.1 mg ofN,N'-disuccinimidyl carbonate. After 4 h, the resultant mixture wasconcentrated in vacuo to provide a yellow solid which was used withoutsubsequent purification.

B. Compound 44

To a solution of 58.1 mg of the resultant crude compound of Example 40Ain 3 mL of dichloromethane was added sequentially, at ambienttemperature under an atmosphere of nitrogen, 0.075 mLdiisopropylethylamine and 46.3 mg of the resultant compound of Example20A. The mixture was stirred for 16 h and then concentrated in vacuo.The residue was taken up in diethyl ether and extracted into 3×25 mL of0.5N HCl. The combined aqueous extracts were adjusted to pH 8 with solidsodium bicarbonate and extracted into 3×25 mL ethyl acetate. Thecombined organic extracts were washed with saturated brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waspurified by thin layer preparative chromatography using (1/2/17/20v/v/v/ 30% ammonium hydroxide/methanol/dichlomethane/diethyl ether)eluent to provide 10.3 mg of the title product. TLC: Rf=0.4, 1/2/17/20v/v/v/ 30% ammonium hydroxide/methanol/dichlomethane/diethyl.ether,HPLC: Rt=11.8 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 45

Compound 45

To a solution of 28.3 mg of the resultant compound of Example 39A in 4mL of dichloromethane was added 1 mL saturated aqueous sodiumbicarbonate solution, 9.2 mg sodium bicarbonate, and 0.013 mL ofbenzenesulfonyl chloride. After 14 h, the resulting mixture was dilutedwith ethyl acetate, washed with saturated brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bythin layer preparative chromatography using 10% diethylether/dichloromethane eluent to provide 19.3 mg of the title product.TLC: Rf=0.84, 25% diethyl ether/dichlormethane, HPLC: Rt=17.2 min; (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 46

Compound 46

To a solution of 47.0 mg (0.140 mmol) of the resultant compound ofExample 39A in 4 mL of dichloromethane was added 1 mL saturated aqueoussodium bicarbonate solution, 17.6 mg of solid sodium bicarbonate, and41.4 mg of 2,4 dimethylthiazole-5-sulfonyl chloride. After 14 h, theresulting mixture was diluted with ethyl acetate, washed with saturatedbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by thin layer preparative chromatography using25% ethyl acetate/dichloromethane eluent to provide 34.6 mg of the titleproduct. TLC: Rf=0.44, 25% diethyl ether/dichloromethane, HPLC: Rt=16.4min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 47

Compound 47

To a solution of 50.7 mg of the resultant compound of Example 39A in 4mL of dichloromethane was added 1 mL saturated aqueous sodiumbicarbonate solution, 15.2 mg of solid sodium bicarbonate, and2-fluorobenzenesulfonyl chloride 35.2 mg. After 14 h, the resultingmixture was diluted with ethyl acetate, washed with saturated brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by thin layer preparative chromatography using 10%diethyl ether/dichloromethane eluent to provide 40.5 mg of the titleproduct. TLC: Rf=0.44, 25% diethyl ether/dichloromethane, HPLC: Rt=17.2min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 48

A. N-succinimidlyl-(S)-3-tetrahydrofuryl carbonate

To a solution of 12.5 mL of 1.93M phosgene in toluene at 0°-5° C. wasadded 1.3 g of (S)-(+)-3-hydroxy-tetrahydrofuran. After stirring for 2h, the reaction mixture was sparged with nitrogen and then concentratedto dryness in vacuo to provide 1.486 g of crude chloroformate. Thismaterial was taken up in 10 mL of acetonitrile and treated sequentiallyat ambient temperature under an atmosphere of nitrogen with 1.17 g ofN-hydroxysuccinimide and 1.41 mL of triethylamine. After stirring for 14h, the reaction mixture was concentrated in vacuo to provide 3.44 g ofthe title product as a white solid.

B. Compound 48

To a solution of 87.2 mg of the resultant compound of Example 40A in 5mL of dichloromethane was added sequentially, at ambient temperatureunder an atmosphere of nitrogen, 0.113 mL diisopropylethylamine and 68mg of the resultant compound of Example 48A. The mixture was stirred for16 h and then concentrated in vacuo. The residue was taken up in ethylacetate and washed with water, 0.5N HCl, saturated sodium bicarbonate,saturated brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography using (3/6/20/65 v/v/v/v/ 30% ammoniumhydroxide/methanol/diethyl ether/dichlomethane) eluent followed bycrystallization from a mixture of dichloromethane, diethyl ether, andhexanes to provide 58 mg of the title product. TLC: Rf=0.17, 75% ethylacetate/dichloromethane, HPLC: Rt=13.1 min.; (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 49

Compound 49

Following the procedure described in Example 83, a solution of theresultant compound of Example 39A in CH₂ Cl₂ is reacted with2,4-difluorobenzenesulfonyl chloride in the presence of water andNaHCO₃. Following dilution with additional CH₂ Cl₂ and aqueous workup,the resultant product is dried over MgSO₄ filtered, and concentrated invacuo. The residue is then purified by silica gel chromatography usingan appropriate solvent system to yield the title product.

EXAMPLE 50

Compound 50

A solution of 30 mg of the resulting compound of Example 58 and 9 μL ofdimethysulfamoyl chloride in 10 mL of CH₂ Cl₂ was reacted in the samemanner as described for Example 14. After workup and purification bypreparative reversed-phase C₁₈ HPLC using a linear gradient of 35% to100% CH₃ CN/H₂ O with 0.1% TFA as eluent, 6.5 mg of the title compoundwas obtained. TLC: Rf=0.2, 3% CH₃ OH in CH₂ Cl₂. HPLC: Rt=15.96 min; (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 51

A. Compound XXI (A=tert-butoxycarbonyl, D'=isobutyl,A'=benzyloxycarbonyl)

To a solution of the resultant compound of Example 39A (2.5 g, 7.43mmol) in CH₂ Cl₂ (50 mL) was added triethylamine (2.1 mL, 14.9 mmol)followed by addition of benzyl chloroformate (1.2 mL, 8.1 mmol). Themixture was allowed to stir at ambient temperature for 6 h. The solutionwas diluted with 1 L of CH₂ Cl₂ and washed with water. The organics weredried over anhydrous MgSO₄, concentrated under reduced pressure, thenpurified via silica gel chromatography. Gradient solvent system: CH₂ Cl₂followed by 3:97 methanol/CH₂ Cl₂. The title compound (2.97 g, wasobtained as a colorless oil. TLC: Rf=0.14, 3:97 methanol/CH₂ Cl₂ ; (¹H)-NMR (CDCl₃) consistent with structure.

B. Compound XXI (A=H, D'=isobutyl, A'=benzyloxycarbonyl, hydrochloridesalt)

To a solution of 1.5 g (3.187 mmol) of the resultant compound of Example51A in ethyl acetate (25 mL) at -20° C. was bubbled anhydrous HCl gasfor 10 min. The ice bath was removed and after an additional 15 min. thereaction is mixture was sparged with nitrogen, then concentrated invacuo to provide 1.29 g of title product as a white solid which was useddirectly for ensuing reaction. TLC: Rf=0.14, 10% methanol/CH₂ Cl₂.

C. Compound XXI (A=(S)-3-tetrahydrofuryloxycarbonyl, D'=isobutyl,A'=benzyloxycarbonyl)

To a solution of 1.077 g of the resultant crude compound of Example 51B(2.647 mmol) in acetonitrile (10 mL) was added sequentially at ambienttemperature under an atmosphere of nitrogen, 1.61 mL (9.263 mmol) ofdiisopropylethylamine and 910 mg (3.97 mmol) of the resultant compoundof Example 48A. After stirring for 3 h, an additional 223 mg (0.973mmol) of the resultant compound of Example 48A was added. The mixturewas stirred for 16 h and then concentrated in vacuo. The residue wastaken up in ethyl acetate and washed with water, 0.5N HCl, saturatedsodium bicarbonate, saturated brine, dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified by lowpressure silica gel column chromatography using a gradient 10% to 25%ethyl acetate in CH₂ Cl₂ eluent to yield 1.025 g of the title product asa white solid. TLC: Rf=0.10, 10% ethyl acetate/CH₂ Cl₂ ; (¹ H)-NMR(CDCl₃) consistent with structure.

D. Compound XXI (A=(S)-3-tetrahydrofuryloxycarbonyl, D'=isobutyl, A'=H)

A solution of 872 mg (1.799 mmol) of the resultant compounds of Example51C in (10 mL) of ethyl alcohol was added, at ambient temperature undera nitrogen atmosphere, to a slurry of 87 mg (10% by weight) of 10%palladium on carbon in (5 mL) ethyl alcohol and hydrogenated for 16 hunder a slight positive pressure of hydrogen. The mixture was filteredand concentrated in vacuo to yield 553.2 mg of the title product as acolorless glass which was used directly for ensuing reaction. TLC:Rf=0.46, 10% methanol/CH₂ Cl₂.

E. Compound 51

To a solution of 72.7 mg (0.207 mmol) of the resultant compound ofExample 51D in CH₂ Cl₂ (4 mL) was added aqueous sodium bicarbonate (1mL), solid sodium bicarbonate 22.6 mg (0.27 mmol), and2-(pyrid-2-yl)-thiophene-5-sulfonyl chloride 64.6 mg, (0.249 mmol).After 14 h, the resulting mixture was diluted with ethyl acetate, washedwith saturated brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by thin layerpreparative chromatography using 15 to 30% ethyl acetate/CH₂ Cl₂ eluentto provide 53 mg of the title product as a white solid. TLC; RF=0.25,25% ethyl acetate/CH₂ Cl₂, HPLC: Rt=15.3 min; (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 52

A. N-hydroxysuccinimidyl-(RS)-3-hydroxyltetrahydrofuryl carbonate

The title compound was prepared as described in Example 48A startingwith 1.0 g of (RS)-3-hydroxy-tetrahydrofuran and yielding 2.33 g of awhite solid.

B. Compound 52

To a solution of 105 mg of the resultant compound of Example 35A in CH₂Cl₂ was added, at ambient temperature under an atmosphere of nitrogen,112 mg of the resultant compound of Example 52A and 126 mgN,N-diisopropylethylamine. The mixture was stirred for 4 h, diluted withCH₂ Cl₂, washed and saturated NaHCO₃ and saturated NaCl, then dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified bylow pressure silica gel chromatography using 5% CH₃ OH in CH₂ Cl₂ aseluent to yield 101.4 mg of product. TLC: Rf=0.52, 5% CH₃ OH in CH₂ Cl₂.HPLC: Rt=15.05 min. (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 53

Compound 53

To a solution of 72.3 mg (0.19 mmol) of the resultant compound ofExample 51D in CH₂ Cl₂ (4 mL) was added aqueous sodium bicarbonate (1mL), solid sodium bicarbonate 19.2 mg (0.228 mmol), and4-acetamido-3-chlorobenzene sulfonyl chloride 61.1 mg, (0.228 mmol).After 14 h, the resulting mixture was diluted with EtOAc, washed withsaturated brine, dried over magnesium sulfate, filtered and concentratedin vacuo. The residue was purified by low pressure silica gel columnchromatography using 20% to 45% EtOAc/CH₂ Cl₂ eluent to provide 49.1 mgof the title product. TLC: RF=0.29, 50% EtOAc/CH₂ Cl₂. HPLC: Rt=13.9min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 54

Compound 54

A solution of 260 mg of the resulting Compound of 39A and 45 mg of3-acetamido-4-fluorobenzenesulfonyl chloride in 10 mL of CH₂ Cl₂ wasreacted in the same manner as described for Example 14. After workup andpurification by preparative reversed-phase C₁₈ HPLC using a lineargradient of 35% to 100% CH₃ CN/H₂ O with 0.1% TFA as eluent, 1.4 mg ofthe title compound was obtained. TLC: Rf=0.25, 5% CH₃ OH in CH₂ Cl₂.HPLC: Rt=15.63 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 55

Compound 55

35.0 mg of the resulting compound of Example 54 was treated with 1 mL of90% aqueous TFA and allowed to stand for 12 h. The mixture wasconcentrated in vacuo and the residue taken up in 10 mL of dry CH₂ Cl₂,treated with 34 μL of DIEA (0.23 mmoles) and 20 mg of1-benzyl-3-tert-butyl-1H-pyrazole-5-carbonyl chloride. The mixture wasstirred for 1.5 h, then diluted with in CH₂ Cl₂, and washed with 1N HCl.After drying over MgSO₄ and concentrating in vacuo, a portion of themixture was purified by preparative reversed-phase C₁₈ HPLC using alinear gradient of 35% to 100% CH₃ CN/H₂ O with 0.1% TFA for elution toobtain 1.1 mg of the title compound. TLC: Rf=0.8, 5% CH₃ OH in CH₂ Cl₂.HPLC: Rt=18.25 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 56

A. S(-)-1-phenylethyl-N-hydroxysuccinimdyl carbonate

The title compound was prepared from 9.5 μL of S(-)-1-phenylethanol and30 m of N,N-disuccinimidyl carbonate as described in Example 44A. Theresulting material was used without subsequent purification; (¹ H)-NMR(CDCl₃) consistent with structure.

B. Compound 56

45.0 mg Of the resulting compound of Example 58 was treated with 1 mL of90% aqueous TFA and allowed to stand for 12 h. The mixture wasconcentrated in vacuo and the residue taken up in 15 mL of dry CH₂ Cl₂,treated with the above mixed anhydride and 65 μL of triethylamine. Themixture was stirred for 14 h then diluted with ethyl acetate and washedwith saturated sodium bicarbonate solution and saturated brine, driedover magnesium sulfate, filtered and concentrated in vacuo. A portion ofthe mixture was purified by preparative reversed-phase C₁₈ HPLC using alinear gradient of mixture was purified by preparative reversed-phaseC₁₈ HPLC using a linear gradient of 35% of 100% CH₃ CN/H₂ O with 0.1%TFA for elution to obtain 1.1 mg of the title compound. TLC: Rf=0.5, 3%CH₃ OH in CH₂ Cl₂ HPLC: Rt=17.44 min; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 57

Compound 57

30 mg of the resultant compound of Example 58 was treated with 1 mL of90% aqueous TFA and allowed to stand for 12 h. The mixture wasconcentrated in vacuo and the residue taken up in 25 mL of dry CH₂ Cl₂,washed and saturated sodium bicarbonate solution, dried over magnesiumsulfate, filtered and concentrated in vacuo. A solution of 14 mg of theresultant free amine in 10 mL of CH₂ Cl₂ was treated with 6 μL ofphenoxyacetyl chloride and 12 μL of triethylamine. The mixture wasstirred under an inert atmosphere for 1 h, then diluted in CH₂ Cl₂ andwashed with 1N HCl. After drying over MgSO₄ and concentrating in vacuo.A portion of the mixture was purified by preparative reversed-phase C₁₈HPLC using a linear gradient of 35% to 100% CH₃ CN/H₂ O with 0.1% TFA aseluant to obtain 16.5 mg of the title compound. TLC: Rf=0.25, 3% MeOH inCH₂ Cl₂. HPLC: Rt=16.6 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 58

Compound 58

A solution of 500 mg of the resulting compound of Example 39A and 370 mgof benzofurazan-4-sulfonyl chloride in 10 mL of CH₂ Cl₂ was reacted inthe same manner as described for Example 14. After workup, the titlecompound was obtained by crystallization from hot ethanol. Furtherpurification of this material by preparative reversed-phase C₁₈ HPLCusing a linear gradient of 35% to 100% CH₃ CN/H₂ O with 0.1% TFA aseluent gave 2.0 mg of the title compound. TLC: Rf=0.35, 3% CH₃ OH in CH₂Cl₂. HPLC: Rt=17.00 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 59

A. R(+)-1-phenylethyl-N-hydroxysuccinimdyl carbonate

The title compound was prepared from R(+)-1-phenylethanol as describedin Example 56A to yield a white solid. The resulting material was useddirectly for subsequent reaction; (¹ H)-NMR (CDCl₃) consistent withstructure.

B. Compound 59

A 36 mg portion of the resultant compound of Example 58 and 0.21 μmol ofthe resulting compound of 59A were reacted in the manner described inexample 56B. After workup and purification by preparative reversed-phaseC₁₈ HPLC using a linear gradient of 35% to 100% CH₃ CN/H₂ O with 0.1%TFA as eluant, 1.0 mg of the title compound was obtained as a whitesolid. TLC: Rf=0.45, 3% MeOH in CH₂ Cl₂. HPLC: Rt=17.34 min; (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 60

Compound 60

To a solution of 70 mg of the resultant compound of Example 51D in 10 mLof CH₂ Cl₂ was added 3 mL of saturated aqueous sodium bicarbonatesolution, 50 mg of sodium bicarbonate, and 53 mg ofbenzofurazan-4-sulfonyl chloride. The mixture was stirred vigorously for4 h, then the resulting mixture was diluted with CH₂ Cl₂, washed withsaturated brine, dried over magnesium sulfate and filtered. Afterconcentration of the mixture in vacuo, the residue was purified by thicklayer silica gel chromatography using 5% MeOH/CH₂ Cl₂ as eluant toobtain 80 mg of the title compound as a white solid. TLC: Rf=0.80, 5%MeOH in CH₂ Cl₂. HPLC: Rt=14.96 min; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 61

Compound 61

To a solution of 35.5 mg (0.076 mmol) of the resultant compound ofExample 16 in 1 mL of dichloromethane was sequentially added 27.6 μL(0.159 mmol) of diisopropylethyl amine and 12 μL (0.083 mmol) of benzylchloroformate. After 1 hour, the mixture was concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography with 50%ethyl acetate/dichloromethane as an eluent to yield 38.7 mg of the titlecompound as a white solid; TLC: Rf=0.63, 50% ethylacetate/dichlormethane; HPLC: Rt=15.45 min; (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 62

A. Benzofurazan-4-sulfonic acid

To a solution of 252.0 mg (1.05 mmol) of o-nitroaniline-m-sulfonic acidsodium salt in 1 mL of water was added 0.52 mL of 2.0N HCl. After 1/2 h,0.68 mL (1.05 mmol) of tertrabutylammonium hydroxide (40% in water) wasadded. After 2 hours, the mixture was concentrated in vacuo. A solutionof the residue in 7 mL of acetic acid was treated with 488.5 mg (1.10mmol) of lead tertraacetate. After 24 hours, the precipitate wasfiltered and washed with small amount of acetic acid. The solid wasfurther dried in vacuo to yield 267.9 mg of product. TLC: Rf=0.09, 10%CH₃ OH/CH₂ Cl₂.

B. Benzofurazan-4-sulfonyl chloride

To a solution of 137.0 mg (0.522 mmol) of triphenylphosphine in 0.5 mLof dichloromethane was slowly added 47 μL (0.594 mmol) of sulfuricchloride at 0° C. The ice-water bath was removed and the crude resultantcompound of Example 62A in 0.5 mL of dichloromethane was added slowly.After 3 hours, the mixture was treated with 30 mL of 50% ether/hexane.The supernatant was decanted into a dry flask and concentrated in vacuo.The residue was purified by filtering through a plug of silica gel with25% ethyl acetate as an eluent to yield 23 mg of product. TLC: Rf=0.6,10% CH₃ OH/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistent with structure.

C. Compound 62

To a solution of 55.7 mg (0.166 mmol) of the resultant compound ofExample 39A in 1 mL of dichloromethane was sequentially added 0.5 mL ofsaturated NaHCO₃, a small amount of solid NaHCO₃ and the resultantcompound of Example 62B. After 3 hours, the mixture was diluted withdichloromethane. The two layers were separated and the aqueous layer wasextracted once with dichloromethane. The combined organic layer waswashed with brine then dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by preparative HPLC to yield 5.3 mg ofthe title compound as a white solid; TLC: Rf=0.40, 50% ethylacetate/dichloromethane; HPLC Rt=16.5 min; (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 63

A.

A solution of 3.0 mg (0.0058 mmol) of the resultant title compound ofExample 62 in 2 mL ethyl acetate was treated with HCl gas (moderatestream) for 3 minutes. The mixture was concentrated in vacuo to yieldthe crude amine hydrochloride salt. TLC: Rf=0.20, 10% CH₃ OH/CH₂ Cl₂.

B. Compound 63

To a solution of the crude resultant compound of Example 63A in 1 mL ofdichloromethane was sequentially added 2.1 uL (0.0121 mmol) ofdiisopropyl ethyl amine and 0.9 uL (0.0064 mmol) of benzylchloroformate. After 1 hour, the mixture was concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography with 90%dichloromethane/methanol as an eluent to yield 2.6 mg of the titlecompound as a white solid; TLC: Rf=0.34, 50% ethylacetate/dichloromethane; HPLC, Rt=17.1 min; (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 64

A. 5-(Dimethylamino)thioxomethoxy)-benzofurazan

To a solution of 500 mg (3.67 mmol) of 5-hydroxybezofurazan in 10 mL ofDMF was added 140 mg (4.59 mmol) of NaH in small portions. The resultingmixture was stirred at room temperature until no more gas evolved. Theflask was then immersed in a cold water bath and 540 mg (4.41 mmol) ofdimethylthiocarbamoyl chloride (from Aldrich) was added. After 5minutes, the water bath was removed the mixture was heated to 80° C. for1 hour. After being cooled to room temperature, the mixture was pouredinto 20 mL of 0.5N NaOH three times and water three times. The solid wasdried in vacuum to yield 580 mg of product that was used in the nextreaction without further purification; TLC: Rf=0.20, 20% ethylacetate/hexane; (¹ H)-NMR (CDCl₃) consistent with structure.

B. 5-((Dimethylamino)carbonyl)thio)-benzofurazan

The crude product, 510 mg (2.28 mmol), from Example 64A was heated to190° C. in a sealed tube. After 5 hours, it was cooled to roomtemperature and ethyl acetate was added. The solution was filteredthrough a plug of a silica and concentrated in vacuo to yield 360 mg ofproduct which was again used in the next reaction without furtherpurification. TLC: Rf=0.20, 20% ethyl acetate/hexane.

C. 5-Mercaptobenzofurazan

To a solution of 357.4 mg (1.60 mmol) of the resultant compound ofExample 64B in 2 mL of methanol was added 7 mL of 6N NaOH. The mixturewas heated to 90° C. for 2 hours. The mixture was poured into 100 mL iceand acidified with concentrated HCl. The slurry was filtered and rinsedthree times with water. The residue was dried in vacuo to yield 145.6 mgof product; TLC: Rf=0.70, 20 ethyl acetate/hexane; (¹ H)-NMR (CDCl₃)consistent with structure.

D. Benzofurazan-5-sulfonyl chloride

Chlorine gas was bubbled through a solution of 39.9 mg (0.26 mmol) ofthe resultant compound of Example 64C in a mixture of 1 mL of ethylacetate and 0.5 mL of water for 3 minutes. The mixture was then washedrepeatedly with brine until no more precipitate formed. The organiclayer was dried over MgSO₄, filtered and concentrated to yield 30 mg ofthe product (52%). TLC: Rf=0.22, 20% ethyl acetate/hexane.

E. Compound 64

A solution of the resultant compounds of Examples 52D and 39A (totalyields) in a mixture of 1 mL of dichloromethane, 0.3 mL of saturatedNaHCO₃ and a small amount of solid NaHCO₃ was stirred at roomtemperature for 2 hours. The solution was diluted with 30 mL ofdichloromethane and the two layers were separated. The aqueous layer wasextracted once with dichloromethane chloride. The combined organic layerwas washed with brine, dried over MgSO₄ and concentrated. The residuewas purified by preparative thin layer chromatography with 90%dichloromethane/ether as an eluent to yield 30 mg of the title productas a white solid; TLC: Rf=0.46, 10% Et₂ O/CH₂ Cl₂, HPLC Rt=17.6 min; (¹H)-NMR (CDCl₃): δ8.45 (s), 1H; 7.96(d), 1H; 7.65 (d), 1H; 7.25(m), 5H;4.65(d), 1H; 3.85(m), 1H; 3.78(m), 1H; 3.30(d), 2H; 3.10(m), 2H;2.90(m), 2H: 1.90(m), 1H; 1.40(s), 9H; 0.90 (d), 6H.

EXAMPLE 65

Compound 65

A solution of 13.1 mg (0.025 mmol) of the resultant compound of Example64E in 1.5 mL of ethyl acetate was treated with gaseous HCl (moderatestream) at 0° C. for 3 minutes. The solvent was removed to yield a solidresidue which was used in the next reaction without furtherpurification; TLC: Rf=0.52, 10% CH₃ OH/CH₂ Cl₂. A solution of thishydrochloride salt (entire yield) in 1 mL of dichloromethane was treatedsequentially with 9.2 μL (0.053 mmol) of diisopropyl ethyl amine and 4.0μL (0.028 mmol) of benzyl chloroformate. After 3 hours, the mixture wasconcentrated and purified by preparative thin layer chromatography with90% dichloromethane/ether as an eluent to yield 11.7 mg of the titlecompound as a white solid; TLC: Rf=0.65, 10% Et₂ O/CH₂ Cl₂ ; HPLCRt=17.6 min; (¹ H)-NMR (CDCl₃ : δ8.45(s), 1H; 7.96(d), 1H; 7.65(d), 1H;7.25(m), 10H; 5.00,(m), 2H; 4.85(d), 1H; 3.86(m), 2H; 3.60(bs), 1H;3.25(m), 12H; 3.05(d), 2H; 2.96(m), 1H: 2.98(m), 1H; 1.88(m), 1H;0.90(dd), 6H.

EXAMPLE 66

Compound 66

A solution of 100 mg (0.46 mmol) of the resultant compound of Example64D and 101 mg (0.286 mmol) of the resultant compound of Example 48A ina mixture of 2 mL of dichloromethane, 0.5 mL of saturated NaHCO₃ andsmall amount of solid NaHCO₃ was stirred at room temperature for 2hours. The solution was diluted with 50 mL of dichloromethane and thetwo layers were separated. The aqueous layer was extracted once withdichloromethane. The combined organic layer was washed with brine, driedover MgSO₄ and concentrated. The residue was purified by preparativethin layer chromatography with 20% ethyl acetate/hexane as an eluent toyield 82 mg of the title product as a slightly impure pale yellow solid.The material was further purified by preparative HPLC with a lineargradient solvent system of 35% to 80% of acetonitrile/water (0.1% TFA)over 80 min. Upon removal the solvents 50 mg of white solid wasobtained. TLC: Rf=0.46, 10% Et₂ O/CH₂ Cl₂ ; HPLC, Rt=17.6 min; (¹ H)-NMR(CDCl₃): δ8.45 (s), 1H; 7.96 (d), 1H; 7.65 (d), 1H; 7.25 (m), 5H; 5.15(m), 1H: 4.85 (d), 1H; 3.82 (m) 4H; 3.68 (d), 1H; 3.20(m), 2H, 3.05 (d),2H; 2.96 (m), 1H; 2.88 (m), 1H; 2.14(m), 1H; 1.92(m), 2H; 1.50(bs), 1H;0.90(dd), 6H.

EXAMPLE 67

Compound 67

Following the procedure described in Example 40B, a solution of theresultant compound of Example 40A in CH₂ Cl₂ is treated withbis-((carboxamido)-amino)-acetic acid, diisopropylethylamine, HOBt, andEDC in a 1:1:1:1:1 molar ratio. the mixture is stirred for 16 h atambient temperature while protected from moisture, then diluted withadditional CH₂ Cl₂ and washed sequentially with H₂ O, saturated NaHCO₃solution and brine, then dried over MgSO₄ and concentrated in vacuo. Theresidue is purified by silica gel chromatography using an appropriateeluant to yield the title product.

EXAMPLE 68

Compound 68

This compound was prepared by the route described in Example 26, exceptthat the reacting amine used was the resulting compound of Example 39A(146 mg, 0.43 mmol) and the acylating agent was 4-fluorophenyl sulphonylchloride (27 mg, 0.14 mmol). After chromatographic purification on asilica gel column using 8% CH₃ OH/CH₂ Cl₂ as eluent, 92.8 mg of thetitle compound was obtained. HPLC: Rt=15.9 minutes. TLC: Rf=0.54, 8%MeOH/CH₂ Cl₂ (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 69

The resulting compound of Example 68 (72.1 mg, 0.167 mmol) was dissolvedin 90% aqueous TFA (3.3 mL), and the reaction mixture stirred for 3hours at room temperature, then was concentrated to dryness. TLC:Rf=0.29, 8% MeOH/CH₂ Cl₂.

B. Compound 69

To a solution of the resulting compound of Example 69A (41.7 mg, 0.09mmol) in CH₂ Cl₂ (2 mL) was added diisopropylethtylamine (47 μl, 0.27mmol) and the resulting compound of Example 48A (33 mg, 0.15 mmol), andthe reaction proceeded for 14 hours at room temperature. The reactionmixture was then concentrated, and the residue was chromatographed on asilica gel column using 8% THF/CH₂ Cl₂ was eluent, yielding the desiredcompound which was further subjected to purification by preparativeHPLC, yielding 7.8 mg of a white solid. HPLC: Rt=13.5 minutes. TLC:Rf=0.36, 8% THF/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 70

Compound 70

A solution of 30 mg of the resulting compound of Example 54 and 17.6 mgof 3-acetamido-4-fluorobenzenesulfonyl chloride in 10 mL of CH₂ Cl₂ wasreacted in the same manner as described for Example 14. After workup andpurification by preparative reversed-phase C₁₈ HPLC using a lineargradient of 35% to 100% CH₃ CN/H₂ O with 0.1% TFA as eluent, 2.0 mg ofthe title compound was obtained. TLC: Rf=0.5, 10% CH₃ OH in CH₂ Cl₂.HPLC: Rt=13.74 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 71

Compound 71

A 30 mg portion of the resultant compound of Example 58 was deprotectedwith trifluoroacetic acid and the resulting compound reacted with 9 μLof dimethysulfamoyl chloride in 10 mL of CH₂ Cl₂ was reacted in themanner described in Example 14. After workup and purification bypreparative reversed-phase C₁₈ HPLC using a linear gradient of 35% to100% CH₃ CN/H₂ O with 0.1% TFA as eluant, 6.5 mg of the title compoundwas obtained. TLC: Rf=0.2, 3% MeOH in CH₂ Cl₂. HPLC: Rt=15.96 min; (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 72

Compound 72

A solution of the resulting compound from the trifluoroacetic aciddeprotection of Example 69A (31 mg, 0.07 mmol) in CH₂ Cl₂ (2 mL) wasadded diisopropylethylamine (47 μl, 0.27 mmol) and dimethylsulfamoylchloride (22 μl, 0.20 mmol), and the reaction proceeded for 16 hours atroom temperature. The reaction mixture was then concentrated, and theresidue was chromatographed on a thick layer silica gel plate (1.0 mm)using 5% THF/CH₂ Cl₂ as eluent, yielding the desired compound which wasfurther subjected to purification by preparative HPLC to yield 7.8 mg ofa white solid. HPLC: Rt=14.8 minutes. TLC: Rf=0.44, 5% THF/CH₂ Cl₂.

EXAMPLE 73

Compound 73

A 43 mg portion of the resultant compound of Example 54 was treated with1 mL of 90% aqueous TFA and allowed to stand for 12 h. The mixture wasconcentrated in vacuo and the residue taken up in 5 mL of CH₂ Cl₂. Tothis solution, 3 mL saturated aqueous sodium bicarbonate and 25 mg of2,5-dimethoxybenzenesulfonyl chloride was added, and the mixture wasstirred for 12 h, warming slowly to ambient temperature. Afterconcentration of the mixture in vacuo, the residue was purified by thicklayer silica gel chromatography using 3% MeOH/CH₂ Cl₂ as eluant followedby preparative reversed-phase C₁₈ HPLC using a linear gradient of 35% to100% CH₃ CN/H₂ O with 0.1% TFA as eluant to obtain 5.5 mg of the titlecompound. TLC: Rf=0.20, 3% MeOH/CH₂ Cl₂. HPLC: Rt=15.15 min; (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 74

A. Compound XXI (A=tert-butoxycarbonyl, D'=cyclopropylmethyl, A'=H)

To a solution of compound XX (A=tert-butoxycarbonyl) (0.8 g, 2.67 mmol)in ethanol (30 mL) was added a solution of KOH (0.18 g, 3.2 mmol) inethanol (20 mL) and the mixture stirred for 45 min at room temperature.In a separate flask, a solution of cyclopropylmethyl-amine hydrochloride(1.44 g, 13.3 mmol) in ethanol (20 mL) was added KOH (0.75 g, 13.3mmol). The mixture was stirred 30 min at room temperature. The solutionswere combined and heated at 85° C. for 3 h. The solution wasconcentrated under reduced pressure and the residue slurried in diethylether and filtered. The ethereal layer was concentrated to give 0.32 gof a white solid; (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound 74

To a solution of the resulting compound of Example 74A (0.1 g, 0.30mmol) in CH₂ Cl₂ (20 mL) was added a saturated solution of sodiumbicarbonate, followed by addition of solid sodium bicarbonate (30 mg,0.36 mmol), then 4-fluorobenzenesulfonyl chloride (0.07 g, 0.36 mmol).The mixture was allowed to stir at room temperature for 4 h. Theorganics were extracted into 250 mL CH₂ Cl₂, dried over anhydrous MgSO₄,concentrated under reduced pressure then purified via medium pressureliquid chromatography using a gradient system of CH₂ Cl₂ followed by0.5:99.5 methanol/CH₂ Cl₂ followed by 1:99 methanol/CH₂ Cl₂. The titlecompound was obtained as 35 mg of a colorless foam. HPLC: Rt=16.8 min.TLC: Rf=0.32, 3:97 methanol/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 75

A. Compound XXI (A=tert-butoxycarbonyl, D'=isopropyl, A'=H)

To a solution of Compound XX (A=tert-butoxycarbonyl) (1.67 mmol) inethanol (10 mL) was treated with isopropylamine (10 mL). The solutionwas heated to 85° C. for 72 h. The solution was filtered thenconcentrated under reduced pressure to give 0.56 g of the title compoundwhich was used without subsequent purification. (¹ H)-NMR (CDCl₃)consistent with structure.

B. Compound 75

To a solution of the resultant compound of Example 75A (0.2 g, 0.65mmol) in CH₂ Cl₂ (10 mL) was added a saturated solution of sodiumbicarbonate (3 mL), followed by addition of solid sodium bicarbonate(0.11 g, 1.31 mmol), then p-fluorobenzenesulfonyl chloride (0.25 g, 1.28mmol). The mixture was stirred overnight at ambient temperature. Theorganics were extracted into 100 mL CH₂ Cl₂, dried over anhydrous MgSO₄,concentrated under reduced pressure then purified via medium pressuresilica gel chromatography using a gradient system of CH₂ Cl₂ followed by1:99 methanol/CH₂ Cl₂. The title compound was obtained as a colorlessfoam 200 mg. TLC: Rf=0.22, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=16.48 min; (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 76

A. Compound XXI (A=tert-butoxycarbonyl, D'=morpholinyl, A'=H)

To a solution of compound XX (A=Boc) in ethanol is added 3 molarequivalents of N-amino morpholine. The mixture is heated under refluxfor 12 h, cooled, and the mixture concentrated in vacuo. The residue ispurified by preparative reversed-phase chromatography using a lineargradient of 5% to 100% acetonitrile/H₂ O as eluant to yield the titlecompound.

B. Compound 76

Following the procedure described in Example 81, a solution of theresultant compound of Example 76A in CH₂ Cl₂ is reacted with4-fluorobenzenesulfonyl chloride in the presence of water and NaHCO₃.Following dilution with additional CH₂ Cl₂ and aqueous workup, theresultant product is dried over MgSO₄, filtered, and concentrated invacuo. The residue is then purified by silica gel chromatography usingan appropriate solvent system to yield the title product.

EXAMPLE 77

A. Compound XXI (A=tert-butoxycarbonyl, D'=4-(N,N-dimethylamino)-benzyl,A'=H)

To a solution of compound XX (A=Boc) in ethanol is added 3 molarequivalents of 4-aminomethyl-(N,N-dimethyl)-aniline. The mixture isheated under reflux for 12 h, cooled, and the mixture concentrated invacuo. The residue is purified by silica gel chromatography using anappropriate solvent system as eluant to yield the title product.

B. Compound 77

Following the procedure described in Example 81, a solution of theresultant compound of Example 77A in CH₂ Cl₂ is reacted with4-fluorobenzenesulfonyl chloride in the presence of water and NaHCO₃.Following dilution with additional CH₂ Cl₂ and aqueous workup, theresultant product is dried over MgSO₄, filtered, and concentrated invacuo. The residue is then purified by silica gel chromatography usingan appropriate solvent system to yield the title product.

EXAMPLE 78

A. Compound XXI (A=tert-butoxycarbonyl, D'=cyclopentyl, A'=H)

To a solution of compound XX (A=Boc) in ethanol is added 10 molarequivalents of cyclopentylamine. The mixture is heated under reflux for12 h, cooled, and the mixture concentrated in vacuo. The residue is usedwithout subsequent purification.

B. Compound 78

Following the procedure described in Example 81, a solution of theresultant compound of Example 78A in CH₂ Cl₂ is reacted with4-fluorobenzenesulfonyl chloride in the presence of water and NaHCO₃.Following dilution with additional CH₂ Cl₂ and aqueous workup, theresultant product is dried over MgsO₄, filtered, and concentrated invacuo. The residue is then purified by silica gel chromatography usingan appropriate solvent system to yield the title product.

EXAMPLE 79

A. Compound XXI (A=tert-butoxycarbonyl, D'=2-(4-pyridyl)ethyl, A'=H)

To a solution of compound XX (A=Boc) in ethanol is added 3 molarequivalents of 4-aminoethylpyridine. The mixture is heated under refluxfor 12 h, cooled, and the mixture concentrated in vacuo. The residue ispurified by preparative reversed-phase chromatography using a lineargradient of 5% to 100% acetonitrile/H₂ O as eluant to yield the titleproduct.

B. Compound 79

Following the procedure described in Example 81, a solution of theresultant compound of Example 79A in CH₂ Cl₂ is reacted with4-fluorobenzenesulfonyl chloride in the presence of water and NaHCO₃.Following dilution with additional CH₂ Cl₂ and aqueous workup, theresultant product is dried over MgSO₄, filtered, and concentrated invacuo. The residue is then purified by silica gel chromatography usingan appropriate solvent system to yield the title product.

EXAMPLE 80

A. 4-Cyanotetrahydro-4H-pyran

Following essentially the procedure of Yoneda, R. "Cyanophosphate: AnEfficient intermediate for Conversion of Carbonyl compounds toNitriles," Tetrahedron Lett., 30, 3681 (1989), a solution oftetrahydro-4H-pyran-one (9.9 g, 97.8 mmol) in dry THF (50 mL) is reactedwith lithium cyanide (9.7 g, 294 mmol) and diethylcyanophosphonate (24g, 146 mmol). The mixture is stirred for 24 h at ambient temperature.The reaction is quenched by the addition of 100 mL H₂ O. The product isextracted into 1.5 L of diethyl ether, dried over anhydrous MgSO₄ thenconcentrated under reduced pressure. The residue is dissolved in dry THF(30 mL) and tert-butyl alcohol (7.25 g, 97.8 mmol). This solution isadded slowly to 75 mL of a 1M solution of SmI₂. The mixture is stirredfor 15 h at ambient temperature. The reaction is quenched by addition of100 mL of saturated aqueous NH₄ Cl. The resulting mixture is extractedwith diethyl ether and the organic layers dried over anhydrous MgSO₄ andconcentrated under reduced pressure. Purification by silica gelchromatography gives the title compound.

B. 4-(aminomethyl)tetrahydro-4H-pyran

To a solution of the compound of the Example 80A (10 g, 89.9 mmol) inabsolute ethanol (200 mL) is added Raney Nickel (2.0 g, 50% slurry inwater). The mixture is stirred for 24 hours at ambient temperature under40 psig of hydrogen. The solution is filtered through celite and thesolution concentrated under reduced pressure. The residue is taken up inether (2L) washed with brine, dried in anh. MgSO₄, then concentratedunder reduced pressure to give the title commpound.

C.(1S,2R)-N-(1-Benzyl-3-(N-(4-(aminomethyl)tetrahydro-4H-pyran))-2-hydroxypropyl)-tertbutoxycarbonylamine

To a solution of the compound of Example 80B (5 g, 48.5 mmol) inabsolute ethanol (20 mL) is added the compound XX (A=Boc) (2.55 g, 9.7mmol). The mixture is stirred for 24 hours at ambient temperature. Thesolution is concentrated under reduced pressure and the crude product ispuffed via column chromatography to give the title compound.

D. Compound XXII (A=Boc, D'=(4-tetrahydro-4H-pyranyl)methyl, A'=H)

To a solution of compound XX (A=Boc) in ethanol is added 3 molarequivalents of the resulting compound of Example 80C. The mixture isheated under reflux for 12 h, cooled, and the mixture concentrated invacuo. The residue is purified by preparative reversed-phasechromotography using a linear gradient of 5% to 100% acetonitrile/H₂ Oas eluant to yield the title compound.

To a solution of compound XX(A=Boc) in ethanol is added 3 molarequivalents of N-amino morpholine. The mixture is heated under refluxfor 12 h, cooled, and the mixture concentrated in vacuo. The residue ispurified by preparative reversed-phase chromatography using a lineargradient of 5% to 100% acetonitrile/H₂ O as eluant to yield the titlecompound.

E. Compound 80

Following the procedure described in Example 81, a solution of theresultant compound of Example 80D in CH₂ Cl₂ is reacted with4-fluorobenzenesulfonyl chloride in the presence of water and NaHCO₃.Following dilution with additional CH₂ Cl₂ and aqueous workup, theresultant product is dried over MgSO₄, filtered, and concentrated invacuo. The residue is then purified by silica gel chromatography toyield the title product.

EXAMPLE 81

A. Compound XXII (P=tert-butoxycarbonyl, D'=isobutyl,E=3,4-dichlorophenyl)

A solution of 316 mg of the resultant compound of Example 39A in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 276 mg of3,4-dichorobenzenesulfonyl chloride and 95 mg of sodium bicarbonate. Themixture was stirred for 14 h, diluted with CH₂ Cl₂, washed withsaturated NaCl then dried over MgSO₄, filtered, and concentrated invacuo. The residue was purified by low pressure silica gelchromatography using 5% diethyl ether/CH₂ Cl₂ as eluent to yield 490 mgof product. TLC: Rf=0.26, 5% diethyl ether in CH₂ Cl₂. HPLC: Rt=18.92min. (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound XXII (P=H, D'=isobutyl, E=3,4-dichlorophenyl, hydrochloridesalt)

A solution of 467 mg of the resultant compound of Example 81A in ethylacetate was treated at -20° C. with HCl gas. The HCl was bubbled throughthe mixture for 20 min over which time the temperature was allowed towarm to 20° C. Nitrogen was then bubbled through the mixture for 15 minand solvent removed in vacuo to yield 412 mg of product as a white solidwhich was used without subsequent purification.

C. Compound 81

A solution of 91 mg of the resultant compound of Example 81B in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 25 mg of allyl chloroformate and 52 mgN,N-diisopropylethylamine. The mixture was stirred for 4 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo to yield 89 mg of the title product as a whitesolid. TLC: Rf=0.53, 5% diethyl ether in CH₂ Cl₂. HPLC: Rt=17.95 min. (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 82

A. (3-Pyridyl)-methyl-4-nitrophenyl-carbonate

To a solution of 3.65 g of bis-(nitrophenyl) carbonate in 25 mL of CH₂Cl₂ at 0° C. was added sequentially 0.97 mL of 3-pyridyl carbinol and1.3 mL of 4-methyl morphine. After stirring at room temperature for 24hours, the resultant mixture was diluted with 100 mL of CH₂ Cl₂, washedwith saturated sodium bicarbonate, water and brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified byfiltration through a plug of silica gel, using 0-40% EtOAc/CH₂ Cl₂ aseluent to provide 1.68 g of the title product. TLC: Rf=0.19, 50%EtOAc/hexane.

B. Compound XXII (P=tert-butoxycarbonyl, D'=isobutyl,E=3,4-benzofurazan)

To a solution of 498.6 mg of the resultant compound of Example 39A in 10mL of CH₂ Cl₂ was added sequentially, 2 mL of saturated sodiumbicarbonate, a small amount of solid sodium bicarbonate and 518.4 mg ofthe resultant compound of Example 64D. After stirring at roomtemperature for 3 hours, the resultant mixture was diluted with 60 mL ofCH₂ Cl₂, washed with saturated sodium bicarbonate and brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography using 5% diethyl ether/hexane aseluent to yield 300 mg of white solid. TLC: Rf=0.80, 50% EtOAc/hexane.

C. Compound XXII (P=H, D'=isobutyl; E=3,4-benzofurazan, hydrochloridesalt.)

A solution of 60.3 mg of the resultant compound of Example 82B in 3 mLof EtOAc at -20° C. was treated with anhydrous HCl gas for 5 min. Theice bath was removed and after an additional 10 min. The reactionmixture was sparged with nitrogen then concentrated in vacuum and theresulting white solid used without subsequent purification forsubsequent reaction.

D. Compound 82

To a solution of the resultant compound of Example 82C (entire yield) in2 mL of CH₂ Cl₂ was added sequentially, 45 μL of diisopropylethylamineand 35.1 mg of the resultant compound of Example 82A. The mixture wasstirred for 24 hours and then concentrated in vacuo. The residue waspurified by preparative thin layer chromatography using 60% ether/CH₂Cl₂ as eluent followed by preparative reversed-phase C₁₈ HPLC using alinear gradient of 40% to 100% CH₃ CN/H₂ O with 0.1% TFA as eluant. Theresultant TFA salt of the title compound was washed with saturatedsodium bicarbonate to yield 6.5 mg of the title compound. TLC: Rf=0.15,20% EtOAc/CH₂ Cl₂. HPLC: Rt=13.52 min. (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 83

A. Compound XXII (A=tert-butoxycaronyl, D'=isobutyl,E=4-acetamido-3-chlorophenyl)

A solution of 339 mg of the resultant compound of Example 39A in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 324 mg of4-acetamido-3-chlorobenzenesulfonyl chloride and 102 mg of sodiumbicarbonate. The mixture was stirred for 14 h, diluted with CH₂ Cl₂,washed with saturated NaCl then dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by low pressure silicagel chromatography using 20% diethyl ether in CH₂ Cl₂ as eluent to yield498 mg of product. TLC: Rf=0.27 (20% diethyl ether in CH₂ Cl₂). HPLC:Rt=16.20 min. (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound XXII (A=H, D'=isobutyl, E=4-acetamido-3-chlorophenyl,hydrochloride salt)

A solution of 474 mg of the resultant compound of Example 83A in ethylacetate was treated at -20° C. with HCl gas. The HCl was bubbled throughthe mixture for 20 min over which time the temperature was allowed towarm to 20° C. Nitrogen was then bubbled through the mixture for 15 minand the solvent was removed in vacuo to yield 421 mg of product as awhite solid which was used without subsequent purification.

C. Compound 83

A solution of 92 mg of the resultant compound of Example 83B in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 24 mg of allyl chloroformate and 52 mgN,N-diisopropylethylamine. The mixture was stirred for 4 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl, then dried over MgSO₄,filtered, and concentrated in vacuo to yield 106 mg of the title productas a white solid. TLC: Rf=0.38 (20% diethyl ether in CH₂ Cl₂). HPLC:Rt=15.28 min. (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 84

Compound XXII (P=tert-butoxycarbonyl, D'=isobutyl, E=3,4-dichlorophenyl)

To a solution of the resultant compound of Example 51D (220 mg, 0.61mmol) in CH₂ Cl₂ (10 mL) was added the 3,4-dichlorobenzenesulfonylchloride (300 mg, 1.22 mmol) followed by the addition of a saturatedsolution of sodium bicarbonate (3 mL) followed by addition of 0.1 g ofsolid sodium bicarbonate. The mixture was stirred at ambient temperatureovernight. The solution was diluted with 100 mL CH₂ Cl₂, the organicsseparated, dried over anhydrous, MgSO₄, and the organics concentratedunder reduced pressure to obtain 0.17 g of crude product. The crudeproduct was purified via medium pressure liquid chromatography using CH₂Cl₂ followed by 0.5:99.5 methanol/CH₂ Cl₂ followed by a 1:99methanol/CH₂ Cl₂ solution as the solvent system to give 103 mg of thetitle compound as a white solid. TLC: Rf=0.56 (3:97 methanol/CH₂ Cl₂),HPLC: Rt=19.78 min, (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 85

A. (3-Tetrahydrofuryl)-methyl-4-nitrophenylcarbonate

To a solution of 1.21 g of p-nitrophenyl chloroformate in 20 mL of CH₂Cl₂ 0° C. was added sequentially, 0.51 g of tetrahydro-3-furanmethanoland 0.66 mL of 4-methyl morpholine. After stirring at room temperaturefor 2 hours. The mixture was stirred for 2 hours and concentrated invacuo. The residue was purified by filtering through a plug of silicagel, using 0-50% EtOAc/CH₂ Cl₂ as eluent to provide 1.17 g of the titleproduct as a pale yellow solid. TLC: Rf=0.20, 50% EtOAc/hexane.

B. Compound 85

To a solution of 70 mg of the resultant compound of Example 81B in 1 mLof THF was added sequentially, 56 μL of diisopropylethylamine and asolution of 46.6 mg of the resultant compound of Example 85A in 1 mL ofTHF. The mixture was stirred for 24 hours and then concentrated invacuo. The residue was diluted with 60 mL of CH₂ Cl₂, washed with 5%sodium bicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated in vacuo to yield 120 mg of crude product. The residue waspurified by preparative thin layer chromatography using 20% EtOAc/CH₂Cl₂ as eluent to yield 82 mg of the title compound. TLC: Rf=0.4, 20%EtOAc/CH₂ Cl₂. HPLC: Rt=17.08 min. (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 86

Compound 86

A solution of 42 mg of the resultant compound of Example 40A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 41 mg of the product of Example 52A and 46 mgN,N-diisopropylethylamine. The mixture was stirred 14 h, diluted withCH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl, then driedover MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by preparative thin layer silica gel chromatography using ethylacetate as eluent to yield 43 mg of product. TLC: Rf=0.44 (20% ethylacetate). HPLC: Rt=13.14 min. (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 87

A. Compound XXII (P=H, D'=isobutyl, E=4-acetamido, 3-fluoro)

A solution of 25 mg of the resultant compound of Example 54 in EtOAc (10mL) at 0° C. was treated with anhydrous hydrogen chloride gas for 10min., and allowed to stand for 12 h while warming to ambienttemperature. The resultant mixture was then concentrated in vacuo toyield compound as a white solid which was used without subsequentpurification for ensuing reaction.

B. Compound 87

A 0.045 mmol portion of the resultant compound of Example 87A was takenup in 5 mL of CH₂ Cl₂. To this solution, 40 μL of diisopropylethylamineand 6 μL of allyl chloroformate were added at 0° C. and the mixture wasstirred for 12 h, while warming slowly to ambient temperature. Theresulting mixture was diluted with CH₂ Cl₂, washed with saturated brine,dried over magnesium sulfate and filtered. After concentrated in vacuo,the residue was purified by preparative reversed-phase C₁₈ HPLC using alinear gradient of 35% to 100% CH₃ CN/H₂ O with 0.1% TFA as eluant toobtain 11.6 mg of the title compound. TLC: Rf=0.20, 5% MeOH/CH₂ Cl₂.HPLC: Rt=14.6 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 88

Compound 88

A 0.033 mmol portion of the resultant compound of Example 87A was takenup in 5 mL of CH₂ Cl₂. To this solution, 26 μL of triethylamine and 12mg of the resultant compound of Example 48A were added and stirred for12 h. The resulting mixture was diluted with CH₂ Cl₂, washed withsaturated sodium bicarbonate solution and saturated brine, dried overmagnesium sulfate and filtered. After concentration of the mixture invacuo, the residue was purified by thick layer silica gel chromatographyusing 5% MeOH/CH₂ Cl₂ as eluant followed by preparative reversed-phaseC₁₈ HPLC using a linear gradient of 35% to 100% CH₃ CN/H₂ O with 0.1%TFA as eluant to obtain 7.5 mg of the title compound. TLC: Rf=0.30, 5%MeOH/CH₂ Cl₂. HPLC: Rt=13.38 min; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 89

Compound 89

A solution of 28 mg of the resultant compound of Example 81B in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 8 mg of n-propyl chloroformate and 17 mgN,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo to yield 31 mg of the title product as a whitesolid. TLC: Rf=0.35 (5% diethyl ether in CH₂ Cl₂). HPLC: Rt=18.12 min.(¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 90

Compound 90

A solution of 28 mg of the resultant compound of Example 83B in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 7 mg of n-propyl chloroformate and 15 mgN,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo to yield 30 mg of the title product as a whitesolid. TLC: Rf=0.47 (20% diethyl ether in CH₂ Cl₂). HPLC: Rt=15.41 min.(¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 91

A. 3-Acetamidobenzene sulfonic acid

A solution of 1.48 g of 3-aminobenzene sulfonic acid in 1:1tetrahydrofuran/water was treated at 0° C. with 1.43 g of sodiumbicarbonate. After 5 min, 1.30 g of acetic anhydride was added dropwiseand the reaction allowed to warm to ambient temperature under anatmosphere of nitrogen over 14 h. The reaction mixture was passedthrough a column of Amberlyst 15 ion exchange resin, eluted with water,and concentrated in vacuo to yield an oil which upon treatment withbenzene and azeotropic removal of water in vacuo yielded 1.8 g of thetitle product as a white crystalline solid. (¹ H)-NMR (CDCl₃) consistentwith structure.

B. 3-Acetamidobenzene sulfonic acid, sodium salt

The resultant compound of Example 91A in water was treated at 0° C. with8.5 mL of 1N sodium hydroxide. The mixture was stirred for 3 h andconcentrated in vacuo to yield an oil which upon treatment with benzeneand azeotropic removal of water in vacuo yielded the title product as atan solid which was used directly in the next reaction.

C. 3-Acetamidobenzenesulfonyl chloride

The resultant compound of Example 91B in CH₂ Cl₂ was treated at 0° C.with 4.5 g of phosphorous pentachloride under an atmosphere of nitrogen.The mixture was stirred 14 h, extracted with CH₂ Cl₂, and concentratedin vacuo to yield 1.7 g of the title product as a brown oil. TLC:Rf=0.21 (1:1 toluene/diethyl ether). (¹ H)-NMR (CDCl₃) consistent withstructure.

D. Compound XXII (A=tert-butoxycarbonyl, D'=isobutyl,E=3-acetamidophenyl)

A solution of 280 mg of the resultant compound of Example 39A in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 252 mg of theresultant compound of Example 91C and 105 mg of sodium bicarbonate. Themixture was stirred for 60 h, diluted with CH₂ Cl₂, washed withsaturated NaCl then dried over MgSO₄, filtered and concentrated invacuo. The residue was purifed by low pressure silica gel chromatographyusing 20% diethyl ether in CH₂ Cl₂ as eluent to yield 156 mg of thetitle product. TLC: Rf=0.14 (20% diethyl ether in CH₂ Cl₂ was). HPLC:Rt=15.39 min. (¹ H)-NMR (CDCl₃) consistent with structure.

E. Compound XXII (A=H, D'=isobutyl, E=3-acetamidophenyl, hydrochloridesalt)

A solution of 123 mg of the resultant compound of Example 91D in ethylacetate was treated at -20° C. with HCl gas. The HCl was bubbled throughthe mixture for 20 min, over which time the temperature was allowed towarm to 20° C. Nitrogen was then bubbled through the mixture for 15 minand solvent removed in vacuo to yield 118 mg of the title product as awhite solid which was used directly in subsequent reactions.

F. Compound 91

A solution of 49 mg of the resultant compound of Example 91E in CH₂ Cl₂was added, at ambient temperature under an atmosphere of nitrogen, to asolution of 48 mg of the resultant compound of Example 48A and 54 mgN,N-diisopropylethylamine in CH₂ Cl₂. The mixture was stirred for 14 h,diluted with CH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl,then dried over MgSO₄, filtered and concentrated in vacuo. The residuewas subjected to preparative thin layer silica gel chromatography using5% CH₃ OH in CH₂ Cl₂ to yield 42 mg of product. TLC: Rf=0.32 (5% CH₃ OHin CH₂ Cl₂). HPLC: Rt=13.27 min. (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 92

Compound 92

To a solution of 63.5 mg of the resultant compound of Example 17B,diastereomer B in 1 mL of THF was added sequentially, 52 μL ofdiisopropylethylamine and a solution of 43.3 mg of the resultantcompound of Example 85A in 1 mL of THF. The mixture was stirred for 24hours and then concentrated in vacuo. The residue was diluted with 60 mLof CH₂ Cl₂, washed with 5% sodium bicarbonate and brine, dried overmagnesium sulfate, filtered and concentrated in vacuo to yield 70.7 mgof crude product. The residue was purified by preparative reversed-phaseC₁₈ HPLC using a linear gradient of 30% to 100% CH₃ CN/H₂ O with 0.1%TFA as eluant to obtain 43.9 mg of the title compound. TLC: Rf=0.29,100% EtOAc. HPLC: Rt=13.24 min; (¹ H) NMR (CDCl₃) consistent withstructure.

EXAMPLE 93

A. N-hydroxysuccinimidyl-(R)-3-hydroxytetrahydrofuryl carbonate

The title compound was prepared as described in Example 48A startingwith 81 mg of (R)-3-hydroxytetrahydrofuran to yield 56 mg of the titleproduct as a white solid. (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound 93

To a solution of 43 mg of the resultant compound of Example 35A in CH₂Cl₂ was added, at ambient temperature under an atmosphere of nitrogen,27 mg of the resultant compound of Example 93A and 39 mgN,N-diisopropylethylamine. The mixture was stirred for 14 h, dilutedwith CH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl, thendried over MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by preparative thin layer silica gel chromatography using 2%CH₃ OH in CH₂ Cl₂ as eluent to yield 45 mg of the title product as awhite solid. TLC: Rf=0.52 (5% CH₃ OH CH₂ Cl₂). HPLC: Rt=14.94 min. (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 94

Compound 94

A solution of 47 mg of the resultant compound of Example 40A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 28 mg of the product of Example 93A and 39 mgN,N-diisopropylethylamine. The mixture was stirred for 14 h, dilutedwith CH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl, thendried over MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by preparative thin layer silica gel chromatography using 5%methanol in CH₂ Cl₂ as eluent to yield 40 mg of the title product as awhite solid. TLC: Rf=0.38 (ethyl acetate). HPLC: Rt=13.09 min. (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 95

Compound 95

To a solution of 72.0 mg (0.189 mmol) of the resultant compound ofExample 51D in CH₂ Cl₂ (4 mL) was added aqueous sodium bicarbonate (1mL), solid sodium bicarbonate 19.1 mg (0.227 mmol), and2,3-dichlorothiophenesulfonyl chloride 57.1 mg, (0.227 mmol). After 14h, the resulting mixture was diluted with EtOAc, washed with saturatedbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by low pressure silica gel columnchromatography using 5 to 12% EtOAc/CH₂ Cl₂ eluent to provide 49.1 mg ofthe title product. TLC: Rf=0.62 25% EtOAc/CH₂ Cl₂, HPLC: Rt=17.3 min; (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 96

A. (4-Acetamido)-phenylmethyl-4-nitrophenylcarbonate

To a solution of 242.8 mg of p-nitrophenyl chloroformate in 5 mL ofacetonitrile at 0° C. was added sequentially, 165.2 mg of4-acetamidobenzyl alcohol and 0.13 mL of 4-methyl morpholine. Themixture was stirred for 24 hours and concentrated in vacuo. The residuewas taken up in CH₂ Cl₂ and washed with 5% sodium bicarbonate and brine,dried over magnesium sulfate, filtered and concentrated in vacuo toyield 320 mg of the title compound. TLC: Rf=0.23, 50% EtOAc/hexane.

B. Compound 96

To solution of the resultant compound of Example 40A in 1 mL of THF wasadded sequentially, 56 μL of diisopropylethylamine and 63 mg of theresultant compound of Example 96A. The mixture was stirred for 24 hoursand then concentrated in vacuo. The residue was purified by preparativethin layer chromatography using 10% methanol/CH₂ Cl₂ as eluent followedby preparative reversed-phase C₁₈ HPLC using a linear gradient of 30% to100% CH₃ CN/H₂ O with 0.1% TFA as eluant to yield 50.2 mg of the titlecompound. TLC: Rf=0.43, 10% methanol/CH₂ Cl₂. HPLC: Rt=13.54 min. (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 97

Compound 97

To solution of 60 mg of the resultant compound of Example 35A in 1 mL ofTHF was added sequentially, 54 μL of diisopropylethylamine and asolution of 48.9 mg of the resultant compound of Example 85A in 1 mLTHF. The mixture was stirred for 24 hours and then concentrated invacuo. The residue was diluted with 60 mL of CH₂ Cl₂, washed with 5%sodium bicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by preparative thinlayer chromatography using 20% EtOAc/CH₂ Cl₂ as eluent to yield 46.9 mgof the title compound. TLC: Rf=0.31, 20% EtOAc/CH₂ Cl₂. HPLC: Rt=15.18min. (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 98

Compound 98

To a solution of 61.0 mg of the resultant compound of Example 35A in 1mL of THF was added sequentially, 49 μL of diisopropylethylamine and asolution of 44 mg of the resultant compound of Example 82A in 1 mL THF.The mixture was stirred for 24 hours and then concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography using 5%methanol/CH₂ Cl₂ as eluent to yield 61.0 mg of a white solid. TLC:Rf=0.19, 5 methanol/CH₂ Cl₂. HPLC: Rt=13.28 min; 13.28 min. (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 99

Compound 99

A solution of 75 mg of the resultant compound of Example 51D and 45 mgof 4-chlorobenzenesulfonyl chloride were reacted in the manner describedin Example 60. After workup and purification by preparativereversed-phase C₁₈ HPLC using a linear gradient of 35% to 100% CH₃ CN/H₂O with 0.1% TFA as eluant, 24.6 mg of the title compound was obtained.TLC: Rf=0.3, 4% MeOH/CH₂ Cl₂. HPLC: Rt=15.87 min; (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 100

Compound 100

A solution of 40 mg of the resultant compound of Example 51D and 45 mgof 4-methoxybenzenesulfonyl chloride were reacted in the mannerdescribed in Example 60. After workup and purification by preparativereversed-phase C₁₈ HPLC using a linear gradient of 35% to 100% CH₃ CN/H₂O with 0.1% TFA as eluant, 21.4 mg of the title compound was obtained asa white solid. TLC: Rf=0.2, 4% MeOH/CH₂ Cl₂. HPLC: Rt=14.85 min; (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 101

Compound 101

This compound was prepared from the resultant compound of Example 128 bytreatment with hydrogen chloride gas and subsequent reaction with theresultant compound of Example 48A in the manner described in Example132. After workup and purification by preparative reversed-phase C₁₈HPLC using a linear gradient of 35% to 100% CH₃ CN/H₂ O with 0.1% TFA aseluant on a portion of the crude mixture, 4.2 mg of the title compoundwas obtained as a white solid. TLC: Rf=0.2, 4% MeOH/CH₂ Cl₂. HPLC:Rt=11.53 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 102

Compound 102

A solution of 36 mg of the resultant compound of Example 40A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 8 mg of methyl chloroformate and 22 mgN,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by low pressuresilica gel chromatography using 30% diethyl ether in CH₂ Cl₂ as eluentto provide 27 mg of the title product as a white solid. TLC: Rf=0.10(30% diethyl ether in CH₂ Cl₂). HPLC: Rt=13.49 min. (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 103

Compound 103

A solution of 29 mg of the resultant compound of Example 81B in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 6 mg of methyl chloroformate and 17 mgN,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by low pressuresilica gel chromatography using 5% diethyl ether/CH₂ Cl₂ as eluent toprovide 29 mg of the title product as a white solid. TLC: Rf=0.24 (5%diethyl ether in CH₂ Cl₂). HPLC: Rt=17.07 min. (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 104

Compound 104

A solution of 31 mg of the resultant compound of Example 35A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 8 mg of methyl chloroformate and 21 mgN,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by low pressuresilica gel chromatography using 5% diethyl ether/CH₂ Cl₂ as eluent toprovide 24 mg of the title product as a white solid. TLC: Rf=0.23 (5%diethyl ether in CH₂ Cl₂). HPLC: Rt=15.41 min. (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 105

A. N-hydroxysuccinimidyl methallyl carbonate

To a solution of 2.9 mL of 1.93M phosgene in toluene at -10° C. wasadded 857 mg of methallyl alcohol. The mixture was stirred for 2 h at-10° C. to produce a 1.9M solution of the title compound which was useddirectly in subsequent reactions.

B. Compound 105

A solution of 39 mg of the resultant compound of Example 40A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 0.05 mL of the resultant compound of Example 105A and 24mg N,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by preparative thinlayer silica gel chromatography using ethyl acetate as eluent to yield18 mg of the title product as a white solid. TLC: Rf=0.67 (ethylacetate). HPLC: Rt=14.97 min. (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 106

Compound 106

A solution of 31 mg of the resultant compound of Example 81B in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 0.04 mL of the resultant compound of Example 105A and 18mg N,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by low pressuresilica gel chromatography using 5% diethyl ether/CH₂ Cl₂ as eluent toprovide 19 mg of the title product as a white solid. TLC: Rf=0.34 (5%diethyl ether/CH₂ Cl₂). HPLC: Rt=18.24 min. (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 107

Compound 107

A solution of 28 mg of the resultant compound of Example 35A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 0.05 mL of the resultant compound of Example 105A and 19mg N,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by low pressuresilica gel chromatography using 5% diethyl ether in CH₂ Cl₂ as eluent toprovide 18 mg of the title product as a white solid. TLC: Rf=0.25 (5%diethyl ether in CH₂ Cl₂). HPLC: Rt=16.68 min. (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 108

Compound 108

To a solution of 62.5 mg of 124B in 1 mL of THF was added sequentially56 μL of diisopropylethylamine and a solution of 49.6 mg of theresultant compound of Example 82A in 1 mL THF. The mixture was stirredfor 24 hours and then concentrated in vacuo. The residue was purified bypreparative thin layer chromatography using 50% EtOAc/CH₂ Cl₂ as eluentfollowed by preparative reversed-phase C₁₈ HPLC using a linear gradientof 30% to 100% CH₃ CN/H₂ O with 0.1% TFA as eluant on a portion of thecrude mixture, 4.2 mg of the title compound was obtained as a whitesolid. TLC: Rf=0.16, 10% methanol/CH₂ Cl₂. HPLC: Rt=13.67 min. (¹ H) NMR(CDCl₃) consistent with structure.

EXAMPLE 109

A. (S)-4-Methoxycarbonyl-oxazlidin-2-one

To a solution of 4.88 g of serine methyl ester hydrochloride in 25 mL ofwater was added 6.94 g of potassium carbonate. The mixture was cooled to0° C. and 19.5 mL of phosgene was added dropwise. After stirring at 0°C. for 3 hours, water was removed to yield a white solid was washed withcopious of CH₂ Cl₂. The organic solution was then dried over magnesiumsulfate, filtered and concentrated to yield 3.26 g of the title productas a clear oil. (¹ H) NMR (D₂ O): δ=3.82 (s, 3H), 4.43 (dd, 1H), 4.53(dd, 1h), 4.67 (t, 1H), 6.29 (s, 1H).

B. (S)-4-Hydroxymethyl-oxazlidin-2-one

To a solution of 3.26 g of the resultant compound of Example 109A in 20mL of ethanol at 0° C. was added 0.85 g of sodium borohydride in smallportions. The ice bath was removed and after additional 3 hours, 20 mLof 2.0N hydrogen chloride was added to the mixture, which was thenconcentrated to yield an oil. The residue was extracted with EtOAc andthe organic solution was dried over magnesium sulfate, filtered andconcentrated to yield 2.50 g of the title compound. (¹ H) NMR (CDCl₃)δ=2.48 (s, 1H), 3.69 (dd, 1H), 4.08 (m, 1H), 4.31 (t, 1H), 4.57 (t, 1H).

C. 4-Nitrophenyl-((S)-4-oxazlidin-2-onyl)-methyl carbonate

To a solution of 1.04 g of p-nitrophenyl chloroformate in 20 mL of CH₂Cl₂ at 0° C. was added sequentially, 0.5 g of the resultant compound ofExample 109B and 0.6 mL of 4-methyl morpholine. The mixture was stirredfor 2 hours at ambient temperature and then concentrated in vacuo. Theresidue was purified by low pressure silica gel column chromatographyusing 20% EtOAc in CH₂ Cl₂ eluent to yield 0.57 g of the title compound.TLC: Rf=0.10, 50% EtOAc/hexane.

D. Compound 109

To a solution of 60 mg of the resultant compound of Example 35A in 1 mLof THF was added sequentially, 56 μL of diisopropylethylamine and asolution of 51.1 mg of the resultant compound of Example 109C in 1 mLacetonitrile. The mixture was stirred for 24 hours and then concentratedin vacuo. The residue was purified by preparative thin layerchromatography using 5% methanol/CH₂ Cl₂ as eluent to yield 60.4 mg ofthe title compound. TLC: Rf=0.38, 5% methanol/CH₂ Cl₂. HPLC: Rt=14.11min. (¹ H) NMR (CDCl₃) consistent with structure.

EXAMPLE 110

Compound 110

To a solution of 60 mg of the resultant compound of Example 40A in 1 mLof acetonitrile was added sequentially, 51 μL of diisopropylethylamineand a solution of 46.8 mg of the resultant compound of Example 109C in 1mL acetonitrile. The mixture was stirred for 48 hours and thenconcentrated in vacuo. The residue was purified by preparative thinlayer chromatography using 10% methanol/CH₂ Cl₂ eluent followed bypreparative reversed-phase C₁₈ HPLC using a linear gradient of 30% to100% CH₃ CN/H₂ O with 0.1% TFA as eluant to yield 16 mg of the titlecompound. TLC: Rf=0.28, 50% EtOAc/CH₂ Cl₂. HPLC: Rt=12.47 min. (¹ H) NMR(CDCl₃) consistent with structure.

EXAMPLE 111

A solution of 0.067 mmol of the resultant compound of Example 114D in 5mL of tetrahydrofuran was added 20 μL of diisopropylethylamine followeddropwise by a solution of the resultant compound of Example 82A in 5 mLof tetrahydrofuran during one hour. The mixture was stirred 16 h andthen concentrated in vacuo. The crude residue was purified by thicklayer silica gel chromatography using 5% MeOH/CH₂ Cl₂ as eluant toobtain 21.8 mg of the title compound. TLC: Rf=0.45, 5% MeOH/CH₂ Cl₂ ; (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 112

A. Compound XXII (A=tert-butoxycarbonyl, D'=isobutyl,E=3-sulfonamidophenyl)

To a solution of 96.6 mg (0.287 mmol) of the resultant compound ofExample 39A in CH₂ Cl₂ (4 mL) was added aqueous sodium bicarbonate (1mL), solid sodium bicarbonate 36.2 mg (0.431 mmol), and m-benzenedisulfonylchloride 86.9 mg, (1.08 mmol). After stirring for 1 h, 30%ammonium hydroxide (10 mL) was added. After 14 h the resulting mixturewas diluted with CH₂ Cl₂, washed with saturated brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by flash chromatography using 0% to 10% methanol/CH₂ Cl₂ eluentto provide 49.3 mg of the title product. (¹ H)-NMR (CDCl₃) consistentwith structure.

B. Compound XXII (A=H, D'=isobutyl, E=3-sulfonamidophenyl, hydrochloridesalt)

A solution of 49.3 mg (0.089 mmol) of the resultant compound of Example112A in EtOAc (10 mL) at -20° C. was treated with anhydrous HCl gas for10 min. The ice bath was removed and after an additional 15 min., thereaction mixture was sparged with nitrogen then concentrated in vacuo toprovide 53.1 mg of title product as the HCl salt. (¹ H)-NMR (CDCl₃)consistent with structure.

C. Compound 112

To a solution of 53.1 mg of the resultant compound of Example 112B(0.089 mmol) in CH₂ Cl₂ (3 mL) was treated sequentially at ambienttemperature under an atmosphere of nitrogen, with 0.031 mL (0.177 mmol)diisopropylethylamine and 24.3 mg (0.106 mmol) of the resultant compoundof Example 48A. The mixture was stirred 16 h and then concentrated invacuo. The residue was taken up in CH₂ Cl₂ and washed with saturatedbrine, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was purified by low pressure silica gel columnchromatography using a gradient 5% to 20% EtOAc in CH₂ Cl₂ as eluent toyield 10.8 mg of the title product. TLC: RF=0.4 25% EtOAc in CH₂ Cl₂.HPLC: Rt=13.3 min; (¹ H) NMR (CDCl₃) consistent with structure.

EXAMPLE 113

A. 3-Furansulfonyl chloride

In flame dried glassware under a nitrogen atmosphere to a solution of428 mg (2.909 mmol) of 3 bromofuran in anhydrous tetrahydrofuran at -78°C. was added 2.0 mL n-butyl lithium (3.2 mmol at 1.6 molar in hexane).After 45 minutes the resultant solution was added via cannula to a 20°C. solution of sulfuryl chloride in diethyl ether (5 mL plus a 2 mLrinse). After 1 h, the reaction was quenched with 0.5N hydrochloric acidand extraced into diethyl ether. The ethereal extracts were washed withsaturated brine, dried over magnesium sulfate, filtered and concentratedin vacuo to provide 158 mg of the title product. (¹ H) NMR (CDCl₃)consistent with structure.

B. Compound XXII (A=tert-butoxycarbonyl, D'=isobutyl, E=3-furyl)

To a solution of 289.7 mg (0.861 mmol) of the resultant compound ofExample 39A in CH₂ Cl₂ (8 mL) was added aqueous sodium bicarbonate (2mL), solid sodium bicarbonate 108 mg (1,292 mmol), and the resultantproduct from Example 113A 157.8 mg, (1.08 mmol). After stirring for 1 h30% ammonium hydroxide (10 mL) was added. After 14 h, the resultingmixture was diluted with CH₂ Cl₂, washed with saturated brine, driedover magnesium sulfate, filtered and concentrated in vacuo. The residuewas purified by flash chromatography using 1% to 15% EtOAc/CH₂ Cl₂.

C. Compound XXII (A=H, D'=isobutyl, E=3-furyl, hydrochloride salt)

A solution of 217.3 mg (0.581 mmol) of the resultant compound of Example113B in EtOAc (15 mL) at -20° C. was treated with anhydrous HCl gas for10 min. The ice bath was removed and after an additional 15 min. thereaction mixture was sparged with nitrogen then concentrated in vacuo toprovide 228 mg of title product as the HCl salt. TLC: Rf=0.52 10%methanol/CH₂ Cl₂.

D. Compound 113

To a solution of 65.3 mg of the resultant compound of Example 113C(0.162 mmol) in CH₂ Cl₂ (3 mL) was treated sequentially at ambienttemperature under an atmosphere of nitrogen, with 0.056 mL (0.324 mmol)diisopropylethylamine and 44.6 mg (0.194 mmol) of the resultant compoundof Example 48A. The mixture was stirred 16 h and then concentrated invacuo. The residue was taken up in CH₂ Cl₂ and washed with saturatedbrine, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was purified by low pressure silica gel columnchromatography using a gradient 3% to 20% EtOAc in CH₂ Cl₂ eluent toyield 10.8 mg of the title product. TLC: Rf=0.6, 25% EtOAc/CH₂ Cl₂.HPLC: Rt=13.9% min; (¹ H) NMR (CDCl₃) consistent with structure.

EXAMPLE 114

A. Aminomethylcyclopentane

To a solution of LiAlH₄ (38 g, 1.0 mole) in diethyl ether (2 L) wasadded cyclopentanecarbonitrile (73.2 g, 0.77 mol) as a solution in 250mL ether. The solution was stirred overnight at ambient temperature andthen quenched by addition of the organics to 3 L of a saturatedpotassium, sodium tartrate solution. The amine was extracted into 3 L ofether, dried over anhydrous K₂ CO₃ then concentrated by distillation toapproximately 400 mL total volume. The crude product was purified viadistillation to give 58.2 g of the title compound as a colorless oil. (¹H)-NMR (CDCl₃) consistent with structure.

B. Compound XXI (P=tert-butoxycarbonyl, D'=cyclopentylmethyl, P'=H)

To the resultant compound of Example 114A (20 g, 0.2 mol) was addedcompound XX (P=Boc) (5.84 g) and the mixture was stirred for 24 h atambient temperature. The solution was concentrated by distillation underreduced pressure. The residue was triturated with hexane and the solidcollected by suction filtration and washed with hexane to give 7.08 g ofa white solid which was used without further purification. TLC: Rf=0.59(1:10:90 concentrated NH₄ OH/methanol/CH₂ Cl₂), (¹ H)-NMR (CDCl₃)consistent with structure.

C. Compound XXII (P=tert-butoxycarbonyl, D'=cyclopentylmethyl,E=4-fluorophenyl)

To a solution of the resultant compound of Example 114B (200 mg, 0.55mmol) in CH₂ Cl₂ (10 mL) was added 4-fluorobenzenesulfonyl chloride (210mg, 1.1 mmol) followed by the addition of a saturated solution of sodiumbicarbonate (3 mL) followed by addition of solid sodium bicarbonate (0.1g, 1.2 mmol). The mixture was allowed to stir at ambient temperatureovernight. The solution was diluted with 100 mL CH₂ Cl₂, the organicsseparated, dried over anhydrous MgSO₄, and the organics concentratedunder reduced pressure to obtain 0.33 g of crude product. This materialwas purified via medium pressure liquid chromatography using CH₂ Cl₂,followed by 0.5:99.5 methanol/CH₂ Cl₂, followed by a 1:99 methanol/CH₂Cl₂ solution as the solvent system to give 120 mg (42% yield) of thetitle compound as a white solid. TLC: Rf=0.48 (3:97 methanol/CH₂ Cl₂);HPLC: Rt=18.22 min, (¹ H)-NMR (CDCl₃) consistent with structure.

D. Compound XXII (P=H, D'=cyclopentylmethyl, E=4-fluorophenyl,hydrochloride salt)

A solution of 266 mg of the resultant compound of Example 114C in ethylacetate was treated at -20° C. with HCl gas for 20 min, during whichtime the temperature was allowed to warm to 20° C. Nitrogen was thenbubbled through the mixture for 15 min and the solvent removed in vacuoto yield 224 mg of white solid which was used directly for ensuingreaction.

E. Compound 114

A solution of 31 mg of the resultant compound of Example 114D in CH₂ Cl₂was treated sequentially, at ambient temperature, under an atmosphere ofnitrogen, with 9 mg of allyl chloroformate and 19 mgN,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed in 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo to yield 34 mg of the title product as a whitesolid. TLC: Rf=0.34 (5% diethyl ether in CH₂ Cl₂). HPLC: Rt=17.21 min.(¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 115

Compound 115

A solution of 31 mg of the resultant compound of Example 114B in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 8 mg of ethyl chloroformate and 19 mgN,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo to yield 35 mg of the title product as a whitesolid. TLC: Rf=0.32 (5% diethyl ether/CH₂ Cl₂). HPLC: Rt=16.86 min. (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 116

A. Compound XXII (A=tert-butoxycarbonyl, D'=cyclopentylmethyl,E=4-chlorophenyl)

The resultant compound of Example 114B (252 mg) was reacted with4-chlorobenzenesulfonyl chloride (175 mg) in the manner described inExample 166A. Workup and purification by silica gel chromatography usingEtOAc/CH₂ Cl₂ as eluant yielded the product as a white solid; (¹ H) NMR(CDCl₃) consistent with structure.

B. Compound XXII (A=H, D'=cyclopentylmethyl, E=4-chlorophenyl,hydrochloride salt)

A solution of 320 mg of the resultant compound of Example 116A in 20 mLof EtOAc was treated with anhydrous HCl gas for 5 min. The reactionmixture was sparged with nitrogen then concentrated in vacuo to yield awhite solid which was used directly for subsequent reaction.

C. Compound 116

To a solution of 63.4 mg of the resultant compound of Example 116B in 1mL of THF was added sequentially 54 μL of diisopropylethylamine and asolution of 39.9 mg of the resultant compound of Example 48A in 1 mLTHF. The mixture was stirred for 24 hours and then concentrated invacuo. The residue was purified by low pressure silica gel columnchromatography using 20% EtOAc in CH₂ Cl₂ eluent to yield 0.62 g of thetitle compound. TLC: Rf=0.71, 40% EtOAc/CH₂ Cl₂. HPLC: Rt=16.88 min. (¹H) NMR (CDCl₃) consistent with structure.

EXAMPLE 117

Compound 117

A solution of 66.1 mg of the resultant compound of Example 116B in 1 mLof THF was treated sequentially with 56 μL of diisopropylethylamine and19.3 μL of allyl chloroformate. The mixture was stirred for 4 hours andconcentrated in vacuo. The residue was taken into 50 mL of EtOAc andwashed with 1.0N HCl, saturated sodium bicarbonate, brine, dried overmagnesium sulfate, filtered and concentrated. The residue was purifiedby low pressure silica gel column chromatography using 20% EtOAc inhexane eluent to yield 69.7 mg of the title compound. TLC: Rf=0.20, 20%EtOAc/hexane. HPLC: Rt=17.83 min. (¹ H) NMR (CDCl₃) consistent withstructure.

EXAMPLE 118

Compound 118

To a solution of 65.3 mg of the resultant compound of Example 116B in 1mL of THF was added sequentially 55 μL of diisopropylethylamine and asolution of 49.2 mg of the resultant compound of Example 82A in 1 mLTHF. The mixture was stirred for 24 hours and concentrated in vacuo. Theresidue was purified by low pressure silica gel column chromatographyusing 40% EtOAc in CH₂ Cl₂ as eluent followed by preparativereversed-phase C₁₈ HPLC using a linear gradient of 40% to 80% CH₃ CN/H₂O for elution to yield 70.7 mg of the title compound. TLC: Rf=0.27, 40%EtOAc/CH₂ Cl₂. HPLC: Rt=14.85 min. (¹ H) NMR (CDCl₃) consistent withstructure.

EXAMPLE 119

Compound 119

A solution of 26 mg of the resultant compound of Example 81B in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 6 mg of ethyl chloroformate and 15 mgN,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetage andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by low pressuresilica gel chromatography using 5% diethyl ether/CH₂ Cl₂ as eluent toprovide 26 mg of the title product as a white solid. TLC: Rf=0.19 (5%diethyl ether in CH₂ Cl₂). HPLC: Rt=17.50 min. (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 120

Compound 120

A solution of 30 mg of the resultant compound of Example 40A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 8 mg of ethyl chloroformate and 18 mgN,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetage andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by preparative thinlayer silica gel chromatography using ethyl acetate as eluent to yield25 mg of the title product as a white solid. TLC: Rf=0.60 (ethylacetate). HPLC: Rt=13.86 min. (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 121

Compound 121

A solution of 26 mg of the resultant compound of Example 35A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 7 mg of ethyl chloroformate and 17 mgN,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by low pressuresilica gel chromatography using 5% diethyl ether/CH₂ Cl₂ as eluent toprovide 22 mg of the title product as a white solid. TLC: Rf=0.14 (5%diethyl ether/CH₂ Cl₂). HPLC: Rt=15.95 min. (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 122

Compound 122

A solution of 27 mg of the resultant compound of Example 35A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 8 mg of allyl chloroformate and 18 mgN,N-diisopropylethylamine. The mixture was stirred for 3 h and thenconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with 0.5N HCl and saturated NaCl then dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by low pressuresilica gel chromatography using 5% diethyl ether in CH₂ Cl₂ as eluent toprovide 23 mg of the title product as a white solid. TLC: Rf=0.33, 5%diethyl ether in CH₂ Cl₂. HPLC: Rt=16.28 min. (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 123

A. Compound XXII (A=tert-butoxycarbonyl, D'=isobutyl,E=3,4-dimethoxyphenyl)

To a solution of 401 mg (1.192 mmol) of the resultant compound ofExample 39A in CH₂ Cl₂ (12 mL) was added aqueous sodium bicarbonate (3mL), solid sodium bicarbonate 130 mg (1.549 mmol), and 3,4-dimethoxybenzenesulfonyl chloride 33.8 mg, (1.43 mmol). After 14 h,the resulting mixture was diluted with EtOAc, washed with saturatedbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by flash chromatography using 5% to 25%EtOAc/CH₂ Cl₂ eluent to provide 440.1 mg of the title product. TLC:Rf=0.72, 20% EtOAc/CH₂ Cl₂.

B. Compound XXII (A=H, D'=isobutyl, E=3,4-dimethoxyphenyl, hydrochloridesalt)

A solution of 440 mg (0.820 mmol) of the resultant compound of Example123A in EtOAc (15 mL) at -20° C. was treated with anhydrous HCl gas for10 min. The ice bath was removed and after an additional 15 min. thereaction mixture was sparged with nitrogen then concentrated in vacuo toprovide 610 mg of title product as the HCl salt. TLC: Rf=0.44, 10%methanol/CH₂ Cl₂.

C. Compound 123

A solution of 38.9 mg of the resultant compound of Example 123B (0.170mmol) in CH₂ Cl₂ (3 mL) was treated sequentially at ambient temperatureunder an atmosphere of nitrogen with 0.049 mL (0.283 mmol)diisopropylethylamine and 66.9 mg (169.6 mmol) of the resultant compoundof Example 48A. The mixture was stirred for 16 h and then concentratedin vacuo. The residue was taken up in CH₂ Cl₂ and washed with saturatedbrine, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was purified by low pressure silica gel columnchromatography using a gradient 10% to 25% diethyl ether in CH₂ Cl₂cluent to yield 57.6 mg of the title product. TLC: Rf=0.39, 25% diethylether/CH₂ Cl₂. HPLC: Rt=14.3 min; (¹ H) NMR (CDCl₃) consistent withstructure.

EXAMPLE 124

A. Compound XXII (A=tert-butoxycarbonyl, D'=isobutyl, E=3,4difluorophenyl)

To a solution of 332.7 mg (0.989 mmol) of the resultant compound ofExample 39A in CH₂ Cl₂ (12 mL) was added aqueous sodium bicarbonate (3mL), solid sodium bicarbonate 125 mg (1.483 mmol), and 3,4difluorobenzensulfonyl chloride 231 mg. (1.088 mmol). After 14 h, theresulting mixture was diluted with CH₂ Cl₂, washed with saturated brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography using 5% to 25% diethylether/CH₂ Cl₂ eluent to provide 313.6 mg of the title product. (¹ H)-NMR(CDCl₃) consistent with structure.

B. Compound XXII (A=H, D'=isobutyl, E=3,4 difluorophenyl, hydrochloridesalt)

A solution of 312.6 mg (0.610 mmol) of the resultant compound of Example124A in EtOAc (15 mL) at -20° C. was treated with anhydrous HCl gas for10 min. The ice bath was removed and after an additional 15 min., thereaction mixture was sparged with nitrogen then concentrated in vacuo toprovide 280 mg of title product as a white solid. TLC: Rf=0.46, 10%methanol/CH₂ Cl₂.

C. Compound 124

To a solution of 64.7 mg of the resultant compound of Example 124B(0.144 mmol) in CH₂ Cl₂ (3 mL) was treated sequentially at ambienttemperature under an atmosphere of nitrogen, with 0.050 mL (0.288 mmol)diisopropylethylamine and 39.6 mg (172.9 mmol)of the resultant compoundof Example 48A. The mixture was stirred for 16 h and then concentratedin vacuo. The residue was taken up in CH₂ Cl₂ and washed with saturatedbrine, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was purified by low pressure silica gel columnchromatography using a gradient 5% to 20% diethyl ether in CH₂ Cl₂eluent to yield 44 mg of the title product. TLC: RF=0.54 25% diethylether/CH₂ Cl₂. HPLC: Rt=15.4 min. (¹ H) NMR (CDCl₃) consistent withstructure.

EXAMPLE 125

Compound 125

This compound was prepared from the resultant compound of Example 146Bin the manner described in Example 88. After workup and purification bypreparative reversed-phase C₁₈ HPLC using a liner gradient of 35% to100% CH₃ CN/H₂ O with 0.1% TFA as eluant, 10.5 mg of the title compoundwas obtained as a white solid. TLC: Rf=0.4, 4% MeOH/CH₂ Cl₂. HPLC:Rt=14.06 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 126

A. Compound XXI (P=tert-butoxycarbonyl, D'=methyl, P'=H)

To a solution compound XX (1.7 mmol) in ethanol (20 mL) was addedmethylamine gas, at ambient temperature, for 30 min. The solution wasstirred overnight, then concentrated under reduced pressure to give 0.47g of the title compound which was used without subsequent purification.TLC: Rf=0.19, 1:10:90 NH₄ OH/methanol/CH₂ Cl₂, (¹ H)-NMR (CDCl₃)consistent with structure.

B. Compound 126

To a solution of the product of Example 126A (0.15 g, 0.51 mmol) in CH₂Cl₂ (10 mL) was added a saturated solution of sodium bicarbonate (3 mL),followed by addition of solid sodium bicarbonate (90 mg, 1.1 mmol),followed by addition of 3,4-dichlorobenzenesulfonyl chloride (0.25 g,1.0 mmol). The mixture was stirred at ambient temperature overnight. Theorganics were extracted into 100 mL CH₂ Cl₂, dried over anhydrous,MgSO₄, concentrated under reduced pressure then purified via mediumpressure silica gel chromatography using a gradient system of CH₂ Cl₂followed by 5:95 ether/CH₂ Cl₂. The title compound was obtained as acolorless foam 210 mg. TLC: Rf=0.42 (3:97 methanol/CH₂ Cl₂), HPLC:Rt=17.2 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 127

Compound 127

To a solution of the product of Example 126A (0.15 g, 0.51 mmol) in CH₂Cl₂ (10 mL) was added a saturated solution of sodium bicarbonate (3 mL),followed by addition of solid sodium bicarbonate (100 mg, 1.0 mmol),followed by addition of 4-fluorobenzenesulfonyl chloride (0.20 g, 1.0mmol). The mixture was stirred at ambient temperature overnight. Theorganics were extracted into 100 mL CH₂ Cl₂, dried over anhydrous,MgSO₄, concentrated under reduced pressure then purified via mediumpressure silica gel chromatography using a gradient system of CH₂ Cl₂followed by 5:95 ether/CH₂ Cl₂. The title compound was obtained as awhite solid 104 mg. TLC: Rf=0.36, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=15.86min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 128

Compound 128

To a solution of the product of Example 126A (0.15 g, 0.51 mmol) in CH₂Cl₂ (6 mL) was added a saturated solution of sodium bicarbonate (3 mL),followed by addition of solid sodium bicarbonate (90 mg, 1.0 mmol),followed by addition of acetamidobenzenesulfonyl chloride (0.24 g, 1.02mmol). The mixture was stirred at ambient temperature overnight. Theorganics were extracted into 100 mL CH₂ Cl₂, dried over anhydrous,MgSO₄, concentrated under reduced pressure then purified via mediumpressure silica gel chromatography using a gradient system of CH₂ Cl₂followed by 5:95 EtOAc/CH₂ Cl₂, followed by 10:90 EtOAc/CH₂ Cl₂. Thetitle compound was obtained as 244 mg of white solid. TLC: Rf=0.13, 3:97methanol/CH₂ Cl₂, HPLC: Rt=13.47 min; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 129

A. Compound XXI (P=tert-butoxycarbonyl, D'=(2-tetrahydrofuryl)-methyl,P'=H)

To a solution compound XX (3.3 mmol) in ethanol (30 mL) was addedtetrahydrofurfurylamine (1.03 mL, 10 mmol). The mixture was warmed to85° C. and stirred overnight. The solution was filtered and the solutionconcentrated under reduced pressure to give 1.29 g of the title compoundwhich was used without subsequent purification. TLC: Rf=0.52, 1:10:90NH₄ OH/methanol/CH₂ Cl₂

B. Compound 129

To a solution of the resultant compound of Example 129A (200 mg, 0.55mmol) in CH₂ Cl₂ (6 mL) was added 4-fluorobenzenesulfonyl chloride (320mg, 1.6 mmol) followed a saturated solution of sodium bicarbonate (3 mL)and solid sodium bicarbonate (0.1 g, 1.2 mmol). The mixture was stirredat ambient temperature overnight. The solution was diluted with 100 mLCH₂ Cl₂, the organics separated, dried over anhydrous MgSO₄, and theorganics concentrated under reduced pressure. The crude product waspurified via medium pressure liquid chromatography using a gradientsolvent system of CH₂ Cl₂ followed by 5:95 ether/CH₂ Cl₂ followed by a10:90 ether/CH₂ Cl₂ solution to give 130 mg of the title compound as awhite solid. TLC: Rf=0.35, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=16.37 min, (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 130

A. Compound XXI (P=tert-butoxycarbonyl, D'=(isobutenyl, P'=H))

To a solution compound XX (P=tert-butoxycarbonyl) (2.5 mmol) in ethanol(30 mL) was added a solution 2-methylallylamine hydrochloride (1.34 g,12.5 mmol) and KOH (0.70 g, 12.5 mmol) in ethanol (20 mL). The mixturestirred 30 min at ambient temperature. The solutions were combined andheated to 85° C. for 24 h. The solution was filtered and concentratedunder reduced pressure to give 0.82 g of the title compound which wasused without subsequent purification. TLC: Rf=0.45, 1:10:90 concentratedNH₄ OH/methanol/CH₂ Cl₂.

B. Compound 130

To a solution of the product of Example 130A (0.20 g, 0.60 mmol) in CH₂Cl₂ (6 mL) was added a saturated solution of sodium bicarbonate (3 mL),followed by solid sodium bicarbonate (0.1 g, 1.2 mmol) and thenp-fluorobenzenesulfonyl chloride (0.35 g, 1.78 mmol). The mixture wasstirred at ambient temperature for 24 h. The organics were extractedinto 100 mL CH₂ Cl₂, dried over anhydrous MgSO₄, concentrated underreduced pressure then purified via medium pressure silica gelchromatography using a gradient system of CH₂ Cl₂, followed by 1:99methanol/CH₂ Cl₂. The title compound was obtained as a white solid 180mg. TLC: Rf=0.35, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=16.82 min; (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 131

Compound 131

To a solution of the resultant compound of Example 130A (200 mg, 0.60mmol) in CH₂ Cl₂ (6 mL) was added 4-acetamidobenzenesulfonyl chloride(410 mg, 1.76 mmol), followed by a saturated solution of sodiumbicarbonate (3 mL) and solid sodium bicarbonate (0.1 g, 1.2 mmol). Themixture was stirred at ambient temperature overnight. The solution wasdiluted with 100 mL CH₂ Cl₂, the organics separated, dried overanhydrous MgSO₄, and the organics concentrated under reduced pressure.The crude product was purified via medium pressure liquid chromatographyusing a gradient solvent system of CH₂ Cl₂, followed by 30:70 EtOAc/CH₂Cl₂ solution to give 140 mg of the title compound as a white solid. TLC:Rf=0.19, 3:97 methanol/CH₂ Cl₂ HPLC: Rt=15.06 min, (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 132

A. Compound XXII (A=H, D'=(2-tetrahydrofuryl)methyl, E=4-fluorophenyl,hydrochloride salt)

To a solution of the resultant compound of Example 129B (30 mg, 0.057mmol) in EtOAc (3 mL) was added 30% w/w HCl in EtOAc (1 mL). The mixturewas stirred overnight at ambient temperature. The solution wasconcentrated under reduced pressure to give 16 mg of the title compoundas a white solid which was used without subsequent purification. TLC:Rf=0.60 (1:10:90 NH₄ OH/methanol/CH₂ Cl₂).

B. Compound 132

To a solution of the resultant compound of Example 132A (16 mg) in CH₂Cl₂ (5 mL) was added triethylamine (0.1 mL, 0.72 mmol) followed by thecompound of Example 48A (20 mg, 0.09 mmol). The mixture was stirred atambient temperature for 24 hours. The solution was concentrated underreduced pressure and the crude product purified via medium pressurecolum chromatography using 20:80 EtOAc/CH₂ Cl₂ as the solvent system togive 7.4 mg. Rf=0.37 (3:97 methanol/CH₂ Cl₂), HPLC: Rt=14.19 min, (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 133

A. Compound XXII (A=tert-butoxycarbonyl, D'=(2-tetrahydrofuryl)-methyl,E=4-acetamidophenyl)

To a solution of the resultant compound of Example 129A (200 mg, 0.55mmol) in CH₂ Cl₂ (6 mL) was added 4-acetamidobenzenesulfonyl chloride(380 mg, 1.6 mmol) followed by a saturated solution of sodiumbicarbonate (3 mL) and solid sodium bicarbonate (0.1 g, 1.2 mmol). themixture was stirred at ambient temperature overnight. The solution wasdiluted with 100 mL CH₂ Cl₂, the organics separated, dried overanhydrous. MgSO₄, and the organics concentrated under reduced pressure.The crude product was purified via medium pressure liquid chromatographyusing a gradient solvent system of CH₂ Cl₂, followed by 10:90 EtOAc/CH₂Cl₂, followed by a 30:70 EtOAc/CH₂ Cl₂ solution to give 120 mg of thetitle compound as a white solid. TLC: Rf=0.13, 3:97 methanol/CH₂ Cl₂ (¹H)-NMR (CDCl₃) consistent with structure.

B. Compound XXII (A=H, D'=(2-tetrahydrofuryl)methyl,E=4-acetamidophenyl, hydrochloride salt)

To a solution of the resultant compound of Example 133A (120 mg 0.22mmol) in EtOAc (5 mL) was added 30% w/w HCl in EtOAc (2 mL). The mixturewas stirred overnight at ambient temperature. The solution wasconcentrated under reduced pressure to give the title compound which wasused without subsequent purification. TLC: Rf=0.50, 1:10:90 NH₄OH/methanol/CH₂ Cl₂.

C. Compound 133

To a solution of the resultant compound of Example 133B in CH₂ Cl₂ (5mL) was added triethylamine (0.2 mL, 1.4 mmol) followed by the compoundof Example 48A (73 mg, 0.32 mmol). The mixture was stirred at ambienttemperature for 24 hours. The solution was concentrated under reducedpressure and the crude product purified via medium pressure columnchromatography using a gradient solvent system of CH₂ Cl₂, followed by1:99 methanol/CH₂ Cl₂, followed by 3:97 methanol/CH₂ Cl₂ as the solventsystem to give 87.8 mg. Rf=0.09, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=12.53min, (₁ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 134

A. Compound XXII (A=H, D'=isobutenyl, E=4-acetamidophenyl, hydrochloridesalt)

To a solution of the resultant compound of Example 131 (40 mg 0.075mmol) in EtOAc (5 mL) was added 30% w/w HCl in EtOAc (2 mL). The mixturewas stirred overnight at ambient temperature. The solution wasconcentrated under reduced pressure to give the title compound, whichwas used without subsequent purification. TLC: Rf=0.38, 1:10:90 NH₄OH/methanol/CH₂ Cl₂.

B. Compound 134

To a solution of the resultant compound of Example 134A in CH₂ Cl₂ (5mL) was added triethylamine (0.1 mL, 0.72 mmol), followed by thecompound of Example 48A (26 mg, 0.11 mmol). The mixture was stirred atambient temperature for 24 hours. The solution was concentrated underreduced pressure and the crude product purified via medium pressurecolumn chromatography using a gradient solvent system of CH₂ Cl₂,followed by 1:99 methanol/CH₂ Cl₂, followed by 3:97 methanol/CH₂ Cl₂ asthe solvent system to give 10.1 mg of the title compound. Rf=0.11 (3:97methanol/CH₂ Cl₂), HPLC: Rt=12.86 min, (₁ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 135

A. Compound XXI (A=H, D'=(isobutenyl, E=4-fluoropheynl, hydrochloridesalt)

To a solution of the resultant compound of Example 130B (50 mg, 0.10mmol) in EtOAc (5 mL) was added 30% w/w HCl in EtOAc (1 mL). The mixturewas stirred overnight at ambient temperature. The solution wasconcentrated under reduced pressure to give the title compound which wasused without subsequent purification. TLC: Rf=0.48, 1:10:90 NH₄OH/methanol/CH₂ Cl₂.

B. Compound 135

To a solution of the resultant compound of Example 135A in CH₂ Cl₂ (5mL) was added triethylamine (0.1 mL, 0.72 mmol), followed by thecompound of Example 48A (35 mg, 0.15 mmol). The mixture was stirred atambient temperature for 24 hours. The solution was concentrated underreduced pressure and the crude product purified via medium pressurecolumn chromatography using a gradient solvent system of CH₂ Cl₂followed by 20:80 EtOAc/CH₂ Cl₂ as the solvent system to give 12 mg.Rf=0.34, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=14.64 min, (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 136

A. Compound XXI (A=tert-butoxycarbonyl, D'=2-furfuryl, A'=H)

To a solution compound XX (2.5 mmol) in ethanol (30 mL) was addedfurfurylamine (0.67 mL, 7.5 mmol) and the mixture was heated to 85° C.for 24 h. The solution was filtered and concentrated under reducedpressure to give 0.80 g of the title compound which was used withoutsubsequent purification. TLC: Rf=0.38, 1:10:90 concentrated NH₄OH/methanol/CH₂ Cl₂.

B. Compound XXII (A=tert-butoxycarbonyl, D'=2-furyl, E=4-fluorophenyl)

To a solution of the product of Example 136A (0.20 g, 0.60 mmol) in CH₂Cl₂ (6 mL) was added a saturated solution of sodium bicarbonate (3 mL),followed by addition of solid sodium bicarbonate (0.1 g, 1.2 mmol), thenp-fluorobenzenesulfonyl chloride (0.32 g, 1.6 mmol). The mixture wasstirred at ambient temperature for 24 h. The organics were extractedinto 100 mL CH₂ Cl₂, dried over anhydrous MgSO₄, concentrated underreduced pressure, then purified via medium pressure silica gelchromatography using a gradient system of CH₂ Cl₂, followed by 1:99methanol/CH₂ Cl₂. The title compound was obtained as a white solid (86.1mg). TLC: Rf=0.17, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=16.5 min; (₁ H)-NMR(CDCl₃) consistent with structure.

C. Compound XXII (A=H, D'=2-furyl, E=4-fluorophenyl, hydrochloride salt)

To a solution of the resultant compound of Example 136B (16 mg, 0.031mmol) in EtOAc (3 mL) was added 30% w/w HCl in EtOAc (1 mL). The mixturewas stirred overnight at ambient temperature. The solution wasconcentrated under reduced pressure to give the title compound, whichwas used without subsequent purification. TLC: Rf=0.48, 1:10:90 NH₄OH/methanol/CH₂ Cl₂.

D. Compound 136

To a solution of the resultant compound of Example 136C in CH₂ Cl₂ (5mL) was added triethylamine (0.1 mL, 0.72 mmol), followed by theresultant compound of Example 48A (11 mg, 0.05 mmol). The mixture wasstirred at ambient temperature for 24 hours. The solution wasconcentrated under reduced pressure and the crude product purified viamedium pressure column chromatography using a gradient solvent system ofCH₂ Cl₂ followed by 20:80 EtOAc/CH₂ Cl₂ as the solvent system to give4.9 mg. TLC: Rf=0.28, (3:97 methanol/CH₂ Cl₂, HPLC: Rt=14.57 min, (₁H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 137

A. Compound XXII (A=tert-butoxycarbonyl, D'=2-furyl,E=4-acetamidophenyl)

To a solution of the resultant compound of Example 136B (200 mg, 0.55mmol) in CH₂ Cl₂ (6 mL) was added 4-acetamidobenzenesulfonyl chloride(390 mg, 1.7 mmol) followed by saturated solution of sodium bicarbonate(3 mL) and solid sodium bicarbonate (0.1 g, 1.2 mmol). The mixture wasstirred at ambient temperature overnight. The solution was diluted with100 mL CH₂ Cl₂, the organics separated, dried over anhydrous. MgSO₄, andthe organics concentrated under reduced pressure. The crude product waspurified via medium pressure liquid chromatography using a gradientsolvent system of CH₂ Cl₂, followed by 10:90 EtOAc/CH₂ Cl₂, followed bya 30:70 EtOAc/CH₂ Cl₂ solution to give 100 mg of the title compound as awhite solid. TLC: Rf=0.19, 3:97 methanol/CH₂ Cl₂, (¹ H)-NMR (CDCl₃)consistent with structure.

B. Compound XXII (A=H, D'=2-furyl, E=4-acetamidophenyl, hydrochloridesalt)

To a solution of the resultant compound of Example 137A (30 mg, 0.054mmol) in EtOAc (3 mL) was added 30% w/w HCl in EtOAc (1 mL). The mixturewas stirred overnight at ambient temperature. The solution wasconcentrated under reduced pressure to give the title compound which wasused without subsequent purification. TLC: Rf=0.37 (1:10:90 NH₄OH/methanol/CH₂ Cl₂).

C. Compound 137

To a solution of the resultant compound of Example 137a in CH₂ Cl₂ (5mL) was added triethylamine (0.1 mL, 0.72 mmol) followed by the compoundof Example 48A (19 mg, 0.083 mmol). The mixture was stirred at ambienttemperature for 24 hours. The solution was concentrated under reducedpressure and the crude product purified via medium pressure columnchromatography using a gradient solvent system of CH₂ Cl₂, followed by1:99 methanol/CH₂ Cl₂, followed by 3:97 methanol/CH₂ Cl₂ as the solventsystem to give 8.5 mg of the title compound. TLC: Rf=0.11 (3:97methanol/CH₂ Cl₂), HPLC: Rt=12.69 min; (₁ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 138

Compound 138

A solution of 75 mg of the resultant compound of Example 51D and 45 mgof 3-chlorobenzenesulfonyl chloride were reacted in the manner describedin Example 60. After workup and purification by preparativereversed-phase C₁₈ HPLC using a linear gradient of 35% to 100% CH₃ CN/H₂O with 0.1% TFA as eluant, 29.7 mg of the title compound was obtained.TLC: Rf=0.3, 4% MeOH/CH₂ Cl₂, HPLC: Rt=15.83 min; (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 139

Compound 139

To a solution of 67.9 mg of the resultant compound of Example 116B in 1mL of THF was added sequentially, 57 μL of diisopropylethylamine and asolution of 52.6 mg of the resultant compound of Example 109C in 1 mLTHF. The mixture was stirred for 24 hours and concentrated in vacuo. Theresidue was purified by preparative thick layer silica gelchromatography using 7% methanol in CH₂ Cl₂ eluent to yield 70.0 mg ofthe title compound. TLC: Rf=0.30, 5% methanol/CH₂ Cl₂. HPLC: Rt=15.78min; (¹ H) NMR (CDCl₃) consistent with structure.

EXAMPLE 140

A. 3(S)-amino-2(syn)-hydroxy-4-phenyl-1-chlorobutane formate salt

To a slurry of 16.33 g of 10% palladium on carbon (25% by weight) inmethanol and tetrahydrofuran (400 mL, 1:1) was added, under N₂, 65.35 gof 3(S)-N-(-benzyloxycarbonyl)-amino-1-chloro-2(syn)-hydroxy-4-phenylbutane (195.77 mmol) as asolution in methanol and tetrahydrofuran (1.2 L). To this slurry wasadded 540 mL of formic acid. After 15 h, the reaction mixture wasfiltered through diatomaceous earth and concentrated to dryness. Theresultant oil was slurried in toluene and evaporated, then trituratedsequentially with diethyl ether and CH₂ Cl₂ to provide 47.64 g ofproduct as a granular tan solid. TLC: Rf=0.17, 5% acetic acid/ethylacetate.

B.3(S)-N-(3(S)-tetrahydrofuryloxycarbonyl)-amino-1-chloro-2(syn)-hydroxy-4-phenylbutane

To a solution of the resultant compound of Example 140A (1.97 g, 7.95mmol) in CH₂ Cl₂ (20 mL) was added a saturated solution of sodiumbicarbonate (5 mL), followed by solid sodium bicarbonate (1.33 g, 17.9mmol), and the resultant compound of Example 48A (2.0 g, 8.7 mmol). Themixture was stirred at ambient temperature overnight. The solution wasdiluted with 200 mL CH₂ Cl₂, the organics separated, dried overanhydrous MgSO₄, and concentrated under reduced pressure. The residuewas recrystallized from ethyl acetate/hexane to give 1.01 g of the titlecompound as a white solid. TLC: Rf=0.35, 3:97 methanol/CH₂ Cl₂. (¹H)-NMR (CDCl₃) consistent with structure.

C. Compound XX (A=3(s)-tetrahydrofuryloxycarbonyl).

To a solution of the resultant compound of Example 140B (1.0 g, 3.2mmol) in absolute ethanol (15 mL) was added solid KOH (0.21 g, 3.8mmol). The mixture was stirred at ambient temperature for 1.0 h. Thesolution was filtered through a pad of Celite then concentrated underreduced pressure. The residue was taken up in ether (100 mL), washedwith brine, dried over MgSO₄, the concentrated under reduced pressure togive 0.88 g of the title compound as a white solid. TLC: Rf=0.49 (3:97methanol/CH₂ Cl₂), (¹ H)-NMR (CDCl₃) consistent with structure.

D. Compound XXI (A=(S)-3-tetrahydrofuryloxycarbonyl,D'=cyclopentylmethyl, A'=H)

The resultant compound of Example 140C (0.88 g, 3.2 mol) was added tothe resultant compound of Example 114A (5.0 g, 50.4 mmol) and stirredfor 24 h at ambient temperature. The solution was concentrated bydistillation under reduced pressure. The residue was triturated withhexane and the solid collected by suction filtration and washed withhexane to give 0.93 g of the title compound. TLC: Rf=0.44, 1:10:90concentrated NH₄ OH/methanol/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistent withstructure.

E. Compound 140

To a solution of the resultant compound of Example 140D (0.93 g, 2.47mmol) in CH₂ Cl₂ (20 mL) was added a saturated solution of sodiumbicarbonate (5 mL) followed by addition of solid sodium bicarbonate(0.42 g, 4.94 mmol) and 4-methoxybenzenesulfonyl chloride (0.61 g, 2.96mmol). the mixture was stirred at ambient temperature for 4 hours. Thesolution was diluted with 200 mL CH₂ Cl₂, the organics separated, driedover anhydrous MgSO₄, and the organics concentrated under reducedpressure. The crude product was purified via medium pressure liquidchromatography using CH₂ Cl₂ followed by 1:99 methanol/CH₂ Cl₂ solutionas the eluent system to give 1.28 g of the title compound as a whitesolid. TLC: Rf=0.26, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=15.66 min, (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 141

A. Compound XXII (A=H, D'=cyclopentylmethyl, E=4-methoxyphenyl,hydrochloride salt)

A solution of 71.3 mg of the resultant compound of Example 166A in EtOAc(25 mL) at 0° C. was treated with anhydrous HCl gas for 10 min., andallowed to stand for 12 h while warming to ambient temperature, thenconcentrated under reduced pressure and the resulting white solid usedwithout purification for subsequent reaction.

B. Compound 141

The resultant compound of Example 141A (0.134 mmol) was reacted withallyl chloroformate in the manner described in Example 87B. Afterconcentration of the mixture in vacuo and workup, the residue waspurified by thick layer silica gel chromatography using 5% MeOH/CH₂ Cl₂as eluant followed by preparative reversed-phase C₁₈ HPLC using a lineargradient of 35% to 100% CH₃ CN/H₂ O with 0.1% TFA as eluant to obtain21.6 mg of the title compound. TLC: Rf=0.45, 5% MeOH/CH₂ Cl₂. HPLC:Rt=16.96 min.

EXAMPLE 142

Compound 142

To a solution of 4.0 g of the resultant compound of Example 141A in 45mL of THF was added sequentially, 1.96 mL of diisopropylethylamine and asolution of 2.68 g of the resultant compound of Example 82A in 45 mLTHF. The mixture was stirred for 24 hours and concentrated in vacuo. Theresidue was taken up in CH₂ Cl₂, washed with saturated sodiumbicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by low pressure silicagel column chromatography using 20% to 40% EtOAc in hexane eluent toyield 3.69 g of the title compound. TLC: Rf=0.41, 50% EtOAc/CH₂ Cl₂.

EXAMPLE 143

Compound 143

A solution of 3.69 g of the resultant compound of Example 142 in 100 mLof ethyl ether was treated with anhydrous HCl gas for 10 min. Thereaction mixture was sparged with nitrogen then filtered. The solid wastaken up in methanol and concentrated to yield 3.71 g of the titlecompound. TLC: Rf=0.62, 90/10/1 CH₂ Cl₂ /MeOH/AcOH, HPLC: Rt=13.87 min.(¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 145

A. Compound XXII (A=tert-butoxycarbonyl, D'=isobutyl,E=2-(5-isoxazoy-3-yl)-thiophene)

To a solution of 342.5 mg (1.02 mmol) of the resultant compound ofExample 39A in CH₂ Cl₂ (8 mL) was added aqueous sodium bicarbonate (2mL), solid sodium bicarbonate 257 mg (3.1 mmol), and5-(isoxazol-3-yl)thiophenesulfonyl chloride 254.2 mg, (1.02 mmol). After14 h, the resulting mixture was diluted with CH₂ Cl₂, washed withsaturated brine, dried over magnesium sulfate, filtered and concentratedin vacuo. The residue was purified by flash chromatography using 5% to25% EtOAc/CH₂ Cl₂ eluent and recrystallized from ether CH₂ Cl₂ toprovide 228.6 mg of the title product. (¹ H)-NMR (CDCl₃) consistent withstructure.

B. Compound XXII (A-H, D'=isobutyl, E=2-(5-isoxazoy-3-ly)-thiopene,hydrochloride salt)

A solution of 228.6 mg (0.416 mmol) of the resultant compound of Example145A in EtOAc (15 mL) at -20° C. was treated with anhydrous HCl gas for10 min. The ice bath was removed and after an additional 15 min, thereaction mixture was sparged with nitrogen then concentrated in vacuo toprovide 223.6 mg of title product as the HCl salt. TLC: Rf=0.48, 10%methanol/CH₂ Cl₂.

C. Compound 145

A solution of 78.5 mg of the resultant compound of Example 145B (0.162mmol) in CH₂ Cl₂ (3 mL) was treated sequentially at ambient temperatureunder an atmosphere of nitrogen with 0.07 mL (0.408 mmol)diisopropylethylamine and 55.6 mg (0.243 mmol) of the resultant compoundof Example 48A. The mixture was stirred 16 h and then concentrated invacuo. The residue was taken up in CH₂ Cl₂ and washed with saturatedbrine, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was purified by preparative HPLC to yield 48.7 mg ofthe title product. TLC: Rf=0.36, 25% EtAOc/CH₂ Cl₂. HPLC: Rt=15.2 min;(¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 146

A. Compound XXI (P=tert-butoxycarbonyl, D'=cyclopentylmethyl,E=4-acetamidophenyl)

To a solution of the resultant compound of Example 114B (300 mg, 0.83mmol) in CH₂ Cl₂ (15 mL) was added 4-acetamidobenzenesulfonyl chloride(580 mg, 2.48 mmol) followed by the addition of a saturated solution ofsodium bicarbonate (4 mL) and solid sodium bicarbonate (0.14 g, 1.67mmol). The mixture was stirred at ambient temperature overnight. Thesolution was diluted with 150 mL CH₂ Cl₂, the organics separated, driedover anhydrous. MgSO₄, and the organics concentrated under reducedpressure. The crude product was purified via medium pressure liquidchromatography using a gradient solvent system of CH₂ Cl₂, followed by5:95 EtOAc/CH₂ Cl₂, followed by 10:90 EtOAc/CH₂ Cl₂ solution to give 310mg of the title compound as a white solid. TLC: Rf=0.10, 3:97methanol/CH₂ Cl₂, HPLC: Rt=15.96 min, (¹ H)-NMR (CDCl₃) consistent withstructure.

B. Compound XXII (P=H, D'=cyclopentylmethyl, E=4-acetamidophenyl,hydrochloride salt)

To a solution of the resultant compound of Example 146A (210 mg, 0.38mmol) was added 30% w/w HCl in EtOAc (15 mL). The mixture was stirredfor 1 hour at ambient temperature. The solution was concentrated underreduced pressure to give 180 mg of the title compound which was usedwithout subsequent purification. TLC: Rf=0.14, 1:10:90 NH₄OH/methanol/CH₂ Cl₂.

C. Compound XXII (P=allyloxycarbonyl, D'=cyclopentylmethyl,E=4-acetamidophenyl)

To a solution of the resultant compound of Example 146B (100 mg, 0.20mmol) in CH₂ Cl₂ (10 mL) was added triethylamine (0.1 mL, 0.72 mmol),followed by allylchloroformate (0.04 mL, 0.3 mmol). The mixture wasstirred at ambient temperature for 24 hours. The solution was dilutedwith 150 mL CH₂ Cl₂, washed with water, dried over anhydrous MgSO₄, andthe organics concentrated under reduced pressure. The crude product waspurified via medium pressure column chromatography using a gradientsolvent system of CH₂ Cl₂, followed by 1:99 methanol/CH₂ Cl₂, followedby 3:97 methanol/CH₂ Cl₂ as the solvent system to give 103 mg. Rf=0.22,3:97 methanol/CH₂ Cl₂, HPLC: Rt=15.29 min, (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 147

Compound 147

To a solution of the resultant compound of Example 146B (80 mg, 0.16mmol) in CH₂ Cl₂ (5 mL) was added triethylamine (0.07 mL, 0.48 mmol),followed by slow addition over 3 hours of the resultant compound ofExample 82A (53 mg, 0.19 mmol) as a solution in CH₂ Cl₂ (3 mL). Themixture was stirred at ambient temperature for 24 hours. The solutionwas diluted with 100 mL CH₂ Cl₂ washed with water, dried over anhydrousMgSO₄, and the organics concentrated under reduced pressure. The crudeproduct was purified via medium pressure column chromatography using agradient solvent system of CH₂ Cl₂, followed by 1:99 methanol/CH₂ Cl₂,followed by 2:98 methanol/CH₂ Cl₂ as the solvent system to give 71.7 mgof the title compound. Rf=0.06, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=12.61min, (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 148

A. Compound XXII (A=tert-butoxycarbonyl, D'=cyclopentylmethyl, E=phenyl)

A solution of 297 mg of the resultant compound of Example 114B in 4:1CH₂ Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 217 mg ofbenzenesulfonyl chloride and 103 mg of sodium bicarbonate. The mixturewas stirred for 6 h, diluted with CH₂ Cl₂, washed with saturated NaClthen dried over MgSO₄, filtered, and concentrated in vacuo to yield 426mg of the title product as a white solid. TLC: Rf=0.32, 5% diethylether/CH₂ Cl₂. (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound XXII (A=H, D'=cyclopentylmethyl, E=phenyl, hydrochloridesalt)

A solution of 400 mg of the resultant compound of Example 148A in ethylacetate was treated at -20° C. with HCl gas for 20 min, during whichtime the temperature was allowed to warm to 20° C. Nitrogen was thenbubbled through the mixture for 15 min and solvent removed in vacuo toyield 349 mg of white solid which was used directly for the ensuingreaction.

C. Compound 148

A solution of 40 mg of the resultant compound of Example 148B in CH₂ Cl₂was added, at ambient temperature under an atmosphere of nitrogen, to asolution of 31 mg of the resultant compound of Example 48A and 35 mgN,N-diisopropylethylamine in CH₂ Cl₂. The mixture was stirred for 14 h,diluted with CH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl,then dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by low pressure silica gel chromatography using 20% diethylether/CH₂ Cl₂ as eluent to provide 45 mg of the title product as a whitesolid. TLC: Rf=0.46, 20% diethyl ether/CH₂ Cl₂. HPLC: Rt=15.78 min. (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 149

A. Compound XXII (A=tert-butoxycarbonyl, D'=cyclopentymethyl,E=3-pyridyl)

To a solution of 153 mg (0.422 mmol) of the resultant compound ofExample 114B in CH₂ Cl₂ (4 mL) was added aqueous sodium bicarbonate (1mL), solid sodium bicarbonate 141.7 mg (1.69 mmol), and the resultantcompound of Example 144A 156.1 mg. (0.879 mmol). After 14 h, theresulting mixture was diluted with CH₂ Cl₂, washed with saturated brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography using 20% to 40% EtOAc/CH₂Cl₂ eluent to provide 64.7 mg of the title product. TLC; Rf=0.24, 20%EtOAc/CH₂ Cl₂.

B. Compound XXII (A=tert-butoxycarbonyl, D'=cyclopentylmethyl,E=3-pyridyl, hydrochloride salt)

A solution of 273.1 mg (0.572 mmol) of the resultant compound of Example149A in EtOAc (15 mL) at -20° C. was treated with anhydrous HCl gas for10 min. The ice bath was removed and after an additional 15 min., thereaction mixture was sparged with nitrogen then concentrated in vacuo.To a solution of the resulting residue in CH₂ Cl₂ (3 mL) was added,sequentially at ambient temperature under an atmosphere of nitrogen,with 0.076 mL (0.437 mmol) diisopropylethylamine and 34.3 mg (0.150mmol) of the resultant compound of Example 48A. The mixture was stirredfor 16 h and then concentrated in vacuo. The residue was taken up in CH₂Cl₂ and washed with saturated brine, dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified by lowpressure silica gel column chromatography using a gradient 20% to 50%EtOAc in CH₂ Cl₂ eluent to yield 11.3 mg of the title product. TLC;Rf=0.15 40% EtOAc/CH₂ Cl₂. HPLC: Rt=13.7 min; (¹ H) NMR (CDCl₃)consistent with structure.

EXAMPLE 150

A. 1-Piperidinesulfonyl chloride

A solution of 4 g of sulfuryl chloride in acetronitrile was treateddropwise with 861 mg of piperidine at ambient temperature under anatmosphere of nitrogen. After complete addition, the mixture wasrefluxed for 18 h, cooled to room temperature and concentrated in vacuoto yield the title product as a red oil. TLC: Rf=0.86, CH₂ Cl₂. (¹H)-NMR (CDCl₃) consistent with structure.

B. Compound XXII (A=tert-butoxycarbonyl, D'=isobutyl, E=piperidinyl)

A solution of 73 mg of the resultant compound of Example 39A in CH₂ Cl₂was treated sequentially, at ambient temperature under an atmosphere ofnitrogen, with 121 mg of the resultant compound of Example 150A and 84mg of N,N-diisopropylethylamine. The mixture was stirred for 14 h,diluted with CH₂ Cl₂, washed with saturated NaCl then dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by lowpressure silica gel chromatography using 5% diethyl ether/CH₂ Cl₂ aseluent to provide 70 mg of the title product as a white solid. TLC:Rf=0.21 (5% diethyl ether in CH₂ Cl₂). HPLC: Rt=17.40 min. (¹ H)-NMR(CDCl₃) consistent with structure.

C. Compound XXII (A=H, D'=isobutyl, E=piperidinyl, hydrochloride salt)

A solution of 70 mg of the resultant compound of Example 150B in ethylacetate was treated at -20° C. with HCl gas for 20 min during which timethe temperature was allowed to warm to 20° C. Nitrogen was then bubbledthrough the mixture for 15 min and solvent removed in vacuo to yield aviscous oil which was used directly for the ensuing reaction.

D. Compound 150

A solution of the resultant compound of Example 150C in CH₂ Cl₂ wasadded, at ambient temperature under an atmosphere of nitrogen, to asolution of 50 mg of the resultant compound of Example 48A and 56 mgN,N-diisopropylethylamine in CH₂ Cl₂. the mixture was stirred for 14 h,diluted with CH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl,then dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by low pressure silica gel chromatography using 20% diethylether/CH₂ Cl₂ as eluent to provide 16 mg of the title product as a whitesolid. TLC: Rf=0.45, (0% diethyl ether/CH₂ Cl₂. HPLC: Rt=15.00 min. (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 151

A. Compound XXII (A tert butoxycarbonyl, D'=cyclopentylmethyl,E=4-trifluormethoxyphenyl)

A solution of 71 mg of the resultant compound of Example 114B in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 76 mg of4-trifluoromethoxybenzensulfonyl chloride and 25 mg of sodiumbicarbonate. The mixture was stirred, 14 h, diluted with CH₂ Cl₂, washedwith saturated NaCl then dried over MgSO₄, filtered, and concentrated invacuo. The residue was purified by low pressure silica gelchromatography using 5% diethyl ether/CH₂ Cl₂ as eluent to provide 92 mgof the title product as a white solid. TLC: Rf=0.34, 5% diethyl ether/CH₂ Cl₂. (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound XXII (A=H, D'=cyclopentylmethyl, E=4-trifluormethoxyphenyl,hydrochloride salt)

A solution of 92 mg of the resultant compound of Example 151A in ethylacetate was treated at -20° C. with HCl gas for 20 min, during whichtime the temperature was allowed to warm to 20° C. Nitrogen was thenbubbled through the mixture for 15 min and solvent removed in vacuo toyield 83 mg of white solid which was used directly for the ensuingreaction.

C. Compound 151

A solution of 22 mg of the resultant compound of Example 151B in CH₂ Cl₂was added, at ambient temperature under an atmosphere of nitrogen, to asolution of 15 mg of the resultant compound of Example 48A and 16 mgN,N-diisopropylethylamine in CH₂ Cl₂. The mixture was stirred for 60 h,diluted with CH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl,then dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by low pressure silica gel chromatography using 20% diethylether/CH₂ Cl₂ as eluent to provide 23 mg of the title product as a whitesolid. TLC: Rf=0.44, 20% diethyl ether/CH₂ Cl₂. HPLC: Rt=16.99 min. (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 152

A. Compound XXII (A=tert-butoxycarbonyl, D'=isobutyl,E=4-trifluormethoxyphenyl)

A solution of 97 mg of the resultant compound of Example 39A in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 113 mg of4-trifluoromethoxybenzenesulfonyl chloride and 36 mg of sodiumbicarbonate. The mixture was stirred for 14 h, diluted with CH₂ Cl₂,washed with saturated NaCl then dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by low pressure silicagel chromatography using 5% diethyl ether/CH₂ Cl₂ as eluent to provide120 mg of the title product as a white solid. TLC: Rf=0.34, 5% diethylether/CH₂ Cl₂. HPLC: Rt=18.54 min. (¹ H)-NMR (CDCl₃) consistent withstructure.

B. Compound XXII (A=H, D'=isobutyl, E=4-trifluormethoxyphenyl,hydrochloride salt)

A solution of 100 mg of the resultant compound of Example 152A in ethylacetate was treated at -20° C. with HCl gas for 20 min, during whichtime the temperature was allowed to warm to 20° C. Nitrogen was thenbubbled through the mixture for 15 min and solvent removed in vacuo toyield 89 mg of white solid which was used directly for ensuing reaction.

C. Compound 152

A solution of 41 mg of the resultant compound of Example 152B in CH₂ Cl₂was added, at ambient temperature under the atmosphere of nigrogen, to asolution of 28 mg of the resultant compound of Example 48A and 32 mgN,N-diisopropylethylamine in CH₂ Cl₂. The mixture was stirred 14 h,diluted with CH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl,then dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by low pressure silica gel chromathography using 5% diethylether/CH₂ Cl₂ as eluent to provide 30 mg of the title product as whitesolid. TLC: Rf-0.08 (5% diethyl ether/CH₂ Cl₂). HPLC: Rt=16.52 min. (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 153

A. Compound XXII (A=tert-butoxycarbonyl, D'=isobutyl, E=4-methoxyphenyl)

To a solution of the resultant compound of Example 39A (600 mg, 1.77mmol) in CH₂ Cl₂ (10 mL) was added 4-methoxybenzenesulfonyl chloride(0.55 g. 2.66 mmol) followed by the addition of a saturated solution ofsodium bicarbonate (3 mL) and 0.30 g of solid sodium bicarbonate. Themixture was stirred at ambient temperature overnight. The solution wasdiluted with 200 mL CH₂ Cl₂, the organics were separated, dried overanhydrous MgSO₄, and the organics concentrated under reduced pressure.The crude product was purified via medium pressure liquid chromatographyusing a gradient solvent system of CH₂ Cl₂ followed by 5:95 ether/CH₂Cl₂ solution to give 630 mg of the title compound as a white solid. TLC:Rf=0.48, 3:97 methanol/CH₂ Cl₂. (¹ H)-NMR (CDCl₃) consistent withstructure.

B. Compound XXII (A=H, D'=isobutyl, E=4-methoxyphenyl, hydrochloridesalt)

To a solution of the resultant compound of Example 153A (0.63 g, 1.24mmol) in EtAc (5 mL) was added 30% w/w HCl in EtOAc (5 mL.) The mixturewas stirred for 6 hours ambient temperature. The solution wasconcentrated under reduced pressure to give 0.59 g of a white solidwhich was used directly for subsequent reaction. TLC Rf=0.12, 3:97methanol/CH₂ Cl₂.

C. Compound XXII (A=(3-pyridyl)-methyloxycarbonyl, D'=isobutyl,E=4-methoxyphenyl)

To a solution of the resultant compound of Example 153B (100 mg, 0.23mmol) in CH₂ Cl₂ (5 mL) was added triethylamine (0.1 mL, 0.72 mmol)followed by slow addition over 3 hours of the resultant compound ofExample 82A (75 mg, 0.27 mmol) as a solution in CH₂ Cl₂ (5 mL). Themixture was stirred at ambient temperature for 24 hours. The organicswas concentrated under reduced pressure and the crude product waspurified via medium pressure column chromatography using a gradientsolvent system of CH₂ Cl₂, followed by 1:99 methanol/CH₂ Cl₂, followedby 3:97 methanol/CH₂ Cl₂ as the solvent system to give 49.3 mg of thetitle compound. Rf=0.33, 3:97 methanol/CH₂ Cl₂. HPLC: Rt=13.18 min, (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 154

Compound 154

To a solution of the resultant compound of Example 153B (100 mg, 0.20mmol) in CH₂ Cl₂ (5 mL) was added triethylamine (0.25 mL, 1.8 mmol)followed by allylchlorofornate (0.1 mL, 0.94 mmol). The mixture wasstirred at ambient temperature for 24 hours. The solution wasconcentrated under reduced pressure and the crude product purified viamedium pressure column chromatography using a gradient solvent system ofCH₂ Cl₂, followed by 1:99 methanol/CH₂ Cl₂ as the solvent system to give94 mg of the title compound. Rf=0.71, 3:97 methanol/CH₂ Cl₂. HPLC:Rt=16.12 min, (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 155

A. N-hydroxysuccinimidyl-1-methoxypropane-3-carbonate

A solution of 355 mg of 2-methylene-1,3-propanediol in acetonitrile (30mL) was added sequentially, at ambient temperature, 65 mg of sodiumhydride and 0.25 mL iodomethane. The mixture was stirred for 12 h andconcentrated in vacuo. The residue was then taken up in 15 mL ofacetonitrile and treated sequentially, at ambient temperature under anatmosphere of nitrogen, with 1.3 g of N,N-disuccinimidyl carbonate and1.6 mL of triethylamine. After stirring for 14 h, the reaction mixturewas concentrated in vacuo and the residue was diluted CH₂ Cl₂, washedwith saturated sodium bicarbonate solution and saturated brine, driedover magnesium sulfate, filtered and concentrated in vacuo. The residuewas purified by silica gel chromatography with EtOAc as eluant to give95 mg of the title compound. (¹ H)-NMR (CDCl₃) consistent withstructure.

B. Compound 155

A solution of 0.056 mmol of the resultant compound of Example 40A wasreacted with the resultant compound of Example 155A in the mannerdescribed in Example 132. After concentration of the mixture in vacuoand workup, the residue was purified by thick layer silica gelchromatography using 7% MeOH/CH₂ Cl₂ as eluant followed by preparativereversed-phase C₁₈ HPLC using a linear gradient of 35% to 100% CH₃ CN/H₂O with 0.1% TFA as eluant to obtain 3.7 mg of the title compound. TLC:Rf=0.45, 7% MeOH/CH₂ Cl₂. HPLC: Rt=13.78 min.

EXAMPLE 156

A. 1-acetylindoline-5-sulfonyl chloride

A 1.02 g portion of 1-acetylindoline was treated with 2 mL ofchlorosulfonic acid at 0° C. The mixture was heated at 60° C. for 2 h,then treated with crushed ice, filtered and dried to give 1.3 g of thetitle compound which was used directly for subsequent reaction. TLC:Rf=0.18, 50% EtOAc/hexane. (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound XXII (P=tert-butoxycarbonyl, D'=cyclopentylmethyl,E=5-(N-acetyl)-indoline)

To a solution of 60 mg of the resultant compound of Example 114B in 15mL of CH₂ Cl₂ was added (5 mL) saturated aqueous sodium bicarbonatesolution, 50.0 mg sodium bicarbonate, and 60 mg of the resultantcompound of Example 156A. After 4 h, the resulting mixture was dilutedwith CH₂ Cl₂, washed with saturated brine, dried over magnesium sulfateand filtered. The mixture was then concentrated in vacuo to give thedesired product which was used directly for subsequent reastion. (¹H)-NMR (CDCl₃) consistent with structure.

C. Compound 156

A solution of 37 mg of the resultant compound of Example 156B in EtOAc(15 mL) at 0° C. was treated with anhydrous hydrogen chloride gas for 10min., and allowed to stand for 12 h while warming to ambienttemperature. This crude material was then reacted with allylchloroformate in the manner described in Example 87B. Afterconcentration of the mixture in vacuo and workup, the residue waspurified by thick layer silica gel chromatography using 70% MeOH/CH₂ Cl₂as eluant followed by preparative reversed-phase C₁₈ HPLC using a lineargradient of 35% to 100% CH₃ CN/H₂ O with 0.1% TFA as eluant to obtain10.5 mg of the title compound. TLC: Rf=0.75, 10% MeOH/CH₂ Cl₂. HPLC:Rt=15.78 min; (¹ H)-NMR (CDCL₃) consistent with structure.

EXAMPLE 157

Compound 157

A solution of 37 mg of the resultant compound of Example 156B in EtOAc(15 mL) at 0° C. was treated with anhydrous hydrogen chloride gas for 10min., and allowed to stand for 12 h while warming to ambienttemperature. This crude material was then reacted with the resultantcompound of Example 48A in the manner described in Example 88. Afterconcentration of the mixture in vacuo, the residue was purified bypreparative reversed-phase C₁₈ HPLC using a linear gradient of 35 to100% CH₃ CN/H₂ O with 0.1% TFA as eluant to obtain 17.9 mg of the titlecompound. TLC: Rf=0.6, 10% MeOH/CH₂ Cl₂. HPLC: Rt=14.68 min; (¹ H)-NMR(CDCL₃) consistent with structure.

EXAMPLE 158

A. Compound XXII (A=tert-butoxycarbonyl, D'=cyclohexylmethyl, E=H)

To a solution of compound XX (A=Boc) (5.0 mmol) in ethanol (20 mL) wasadded cyclohexylmethylamine (3.25 mL, 2.83 mmol) and the mixture wasstirred for 3 hours at ambient temperature. The solution was filteredand concentrated under reduced pressure to give 1.49 g of a white solidwhich was used directly for subsequent reaction. TLC: Rf=0.14, 3:97methanol/CH₂ Cl₂. (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound XXII (A=tert-butoxycarbonyl, D'=cyclohexylmethyl,E=4-methoxyphenyl)

To a solution of the resultant compound of Example 158A (400 mg, 1.06mmol) in CH₂ Cl₂ (10 mL) was added 4-methoxybenzenesulfonyl chloride(0.66 g, 3.1 mmol) followed by addition of a saturated solution ofsodium bicarbonate (3 mL) and 0.18 g of solid sodium bicarbonate. Themixture was stirred at ambient temperature overnight. The solution wasdiluted with 200 mL CH₂ Cl₂, the organics separated, dried overanhydrous MgSO₄, and the organics concentrated under reduced pressure.The crude product was purified via medium pressure liquid chromatographyusing CH₂ Cl₂, followed by 1:99 methanol/CH₂ Cl₂ as the solvent systemto give 340 mg of the title compound as a white solid. TLC: Rf=0.39,3:97 methanol/CH₂ Cl₂, (¹ H)-NMR (CDCL₃) consistent with structure.

C. Compound XXI (A=H, D'=cyclohexylmethyl, E=4-methoxyphenyl,hydrochloride salt)

To a solution of the resultant compound of Example 158B (0.34 g, 0.62mmol) in EtOAc (10 mL) was added 30% w/w HCl in EtOAc (5 mL). Themixture was stirred for 3 hours at ambient temperature. The solution wasconcentrated under reduced pressure to give 0.3 g of a white solid whichwas used directly for subsequent reaction. TLC: Rf=0.12, 3:97methanol/CH₂ Cl₂.

D. Compound 158

To a solution of the resultant compound of Example 158C (100 mg, 0.21mmol) in CH₂ Cl₂ (8 mL) was added triethylamine (0.2 mL, 1.44 mmol)followed by the resultant compound of Example 48A (71 mg, 0.31 mmol).The mixture was stirred at ambient temperature for 6 hours. The solutionwas diluted with CH₂ Cl₂, (200 mL) washed with a saturated solution ofsodium bicarbonate (30 mL), the organics separated, dried over anhydrousMgSO₄ and concentrated under reduced pressure and the crude productpurified via medium pressure column chromatography using a gradientsolvent system of CH₂ Cl₂ followed by 10:90 EtOAc/CH₂ Cl₂ as the solventsystem to give 84.9 mg of the title compound. TLC: Rf=0.48, 3:97methanol/CH₂ Cl₂, HPLC: Rt=16.35 min; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 159

A. Compound XXII (A=tert-butoxycarbonyl, D'=cyclohexylmethyl,E=4-fluorophenyl)

To a solution of the resultant compound of Example 158A (400 mg, 1.06mmol) in CH₂ Cl₂ (10 mL) was added 4-fluorobenzenesulfonyl chloride(0.62 g, 3.2 mmol) followed by addition of a saturated solution ofsodium bicarbonate (3 mL) and 0.18 g of solid sodium bicarbonate. Themixture was stirred at ambient temperature overnight. The solution wasdiluted with 200 mL CH₂ Cl₂, the organics separated, dried overanhydrous MgSO₄, and the organics concentrated under reduced pressure.The crude product was purified via medium pressure liquid chromatographyusing CH₂ Cl₂ followed by 1:99 methanol/CH₂ Cl₂ solution as the solventsystem to give 280 mg of a white solid. TLC: Rf=0.47, 3:97 methanol/CH₂Cl₂, (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound XXII (A=H, D'=cyclohexylmethyl, E=4-fluorophenyl,hydrochloride salt)

To a solution of the resultant compound of Example 159A (0.28 g, 0.52mmol) was added 30% w/w HCl in EtOAc (10 mL). The mixture was stirredfor 3 hours at ambient temperature. The solution was concentrated underreduced pressure to give 0.23 g of a white solid which was used directlyfor subsequent reaction. TLC: Rf=0.13, (3:97 methanol/CH₂ Cl₂, (¹ H)-NMR(CDCL₃) consistent with structure.

C. Compound 159

To a solution of the resultant compound of Example 159C (100 mg, 0.21mmol) in CH₂ Cl₂ (8 mL) was added triethylamine (0.2 mL, 1.44 mmol)followed by the resultant compound of Example 48A (73 mg, 0.32 mmol).The mixture was stirred at ambient temperature for 6 hours. The solutionwas diluted with CH₂ Cl₂, (200 mL) washed with saturated solution ofsodium bicarbonate (30 mL), dried over anhydrous MgSO₄, the organicsconcentrated under reduced pressure and the crude product purified viamedium pressure column chromatography using a gradient solvent system ofCH₂ Cl₂, followed by 10:90 EtOAc/CH₂ Cl₂ as the solvent system to give54 mg of the title compound. TLC: Rf=0.46, 3:97 methanol/CH₂ Cl₂, HPLC:Rt=16.48 min; (¹ H)-NMR (CDCL₃) consistent with structure.

EXAMPLE 160

A. Compound XXII (A=tert-butoxycarbonyl, D'=cyclohexylmethyl,E=4-acetamidophenyl)

To a solution of the resultant compound of Example 158A (400 mg, 1.06mmol) in CH₂ Cl₂ (10 mL) was added 4-acetamidobenzenesulfonyl chloride(0.75 g, 3.2 mmol) followed by addition of a saturated solution ofsodium bicarbonate (3 mL) and 0.18 g of solid sodium bicarbonate. Themixture was stirred at ambient temperature overnight. The solution wasdiluted with 200 mL CH₂ Cl₂, the organics separated, dried overanhydrous MgSO₄, and the organics concentrated under reduced pressure.The crude product was purified via medium pressure liquid chromatographyusing CH₂ Cl₂, followed by 1:99 methanol/CH₂ Cl₂ and 2:98 methanol/CH₂Cl₂ as the solvent system to give 290 mg of the title compound as awhite solid. TLC: Rf=0.14, 3:97 methanol/CH₂ Cl₂, (¹ H)-NMR (CDCl₃)consistent with structure.

B. Compound XXII (A=H, D'=cyclohexylmethyl, E=4-acetamidophenyl,hydrochloride salt)

To the resultant compound of Example 160A (0.29 g, 0.51 mmol) was added30% w/w HCl in EtOAc (10 mL). The mixture was stirred for 3 hours atambient temperature. The solution was concentrated under reducedpressure to give 0.28 g of a white solid which was used directly forsubsequent reaction. TLC: Rf=0.10, 3:97 methanol/CH₂ Cl₂.

C. Compound 160

To a solution of the resultant compound of Example 160B (100 mg, 0.20mmol) in CH₂ Cl₂ (8 mL) was added triethylamine (0.2 mL, 1.44 mmol)followed by the resultant compound of Example 48A (67 mg, 0.30 mmol).The mixture was stirred at ambient temperature for 6 hours. The solutionwas diluted with CH₂ Cl₂, (200 mL) washed with saturated solution ofsodium bicarbonate (30 mL), dried over anhydrous MgSO₄, the organicsconcentrated under reduced pressure and the crude product purified viamedium pressure column chromatography using a gradient solvent system ofCH₂ Cl₂, followed by 10:90 EtOAc/CH₂ Cl₂, followed by 20:80 EtOAc/CH₂Cl₂ as the solvent system to give 56.8 mg of a white solid. TLC:Rf=0.17, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=14.65 min; (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 161

A. 4-Morpholinesulfonyl chloride

A solution of 4.6 g of sulfuryl chloride in acetonitrile was treateddropwise with 996 mg of morpholine at ambient temperature under anatmosphere of nitrogen. After complete addition, the mixture wasrefluxed for 16 h, cooled to room temperature, and concentrated in vacuoto yield the title product as a red oil. TLC: Rf=0.65 CH₂ Cl₂. (¹ H)-NMR(CDCl₃) consistent with structure.

B. Compound XXII (A-tert-butoxycarbonyl, D'=isobutyl, E=morpholinyl)

A solution of 98 mg of the resultant compound of Example 39A in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 270 mg of theresultant compound of Example 161A and 122 mg of sodium bicarbonate. Themixture was stirred for 14 h, diluted with CH₂ Cl₂, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by lowpressure silica gel chromatography using CH₂ Cl₂ as eluent followed bypreparative HPLC to provide 22 mg of the title product as an oily solid.TLC: Rf=0.46, 20% diethyl ether/CH₂ Cl₂. HPLC: Rt=15.50 min. (¹ H)-NMR(CDCl₃) consistent with structure.

C. Compound XXII (A=H, D'=isobutyl, E=morpholinyl, hydrochloride salt)

A solution of 22 mg of the resultant compound of Example 161B in ethylacetate was treated at -20° C. Nitrogen was then bubbled through themixture for 15 min and solvent removed in vacuo to yield an oilysemi-solid mass which was used directly for the ensuing reaction.

D. Compound 161

A solution of the resultant compound of Example 161C in CH₂ Cl₂ wasadded, at ambient temperature under an atmosphere of nitrogen, to asolution of 16 mg of the resultant compound of Example 48A and 18 mgN,N-diisopropylethylamine in CH₂ Cl₂. The mixture was stirred for 14 h,diluted with CH₂ Cl₂, washed and saturated with NaHCO₃ and saturatedNaCl, then dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by preparative HPLC to provide 21 mg of the titleproduct as an oily solid. TLC: Rf=0.22, 20% diethyl ether/CH₂ Cl₂. HPLC:Rt=13.01 min. (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 162

Compound 162

A solution of 30 mg of the resultant compound of Example 166A wasdeprotected with hydrogen chloride gas and the resultant compound wasreacted with the resultant compound of Example 155A in the mannerdescribed in Example 155B. After concentration of the mixture in vacuoand workup, the residue was purified by thick layer silica gelchromatography using 5% MeOH/CH₂ Cl₂ as eluant, followed by preparativereversed-phase C₁₈ HPLC using a linear gradient of 35% to 100% CH₃ CN/H₂O) with 0.1% TFA as eluant to obtain 6.2 mg of the title compound. TLC:Rf=0.65, 5% MeOH/CH₂ Cl₂. HPLC: Rt=15.93 min (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 163

Compound 163

A 120.3 mg portion of the resultant compound of Example 153B was reactedwith the resultant compound of Example 82A as described in Example 82B.After workup and concentration in vacuo, the residue was purified by lowpressure silica gel column chromatography using 50% EtOAc in CH₂ Cl₂eluent, followed by preparative reversed-phase C₁₈ HPLC using a lineargradient of 40% to 100% acetonitrile/water for elution to obtain 44.3 mgof the title compound. TLC: Rf=0.18, 50% EtOAc/CH₂ Cl₂. HPLC: Rt=13.13min; (¹ H) NMR (CDCl₃) consistent with structure.

EXAMPLE 164

A. N-hydroxysuccinimidyl-(2-phenyl)ethyl carbonate

A solution of 306 mg of phenethyl alcohol and 535 mg ofN,N'-disuccinimidyl carbonate in acetonitrile was treated, at ambienttemperature under an atmosphere of nitrogen, with 810 mg ofN,N-diisopropylethylamine. The mixture was stirred for 60 h andconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with saturated NaHCO₃, saturated NaCl, then dried over MgSO₄,filtered, and concentrated in vacuo to yield the title product as ayellow oil. TLC: Rf=0.40 (5% methanol in CH₂ Cl₂). (¹ H)-NMR (CDCl₃)consistent with structure.

B. Compound 164

A solution of 81 mg of the resultant compound of Example 164A in CH₂ Cl₂was added, at ambient temperature under an atmosphere of nitrogen, to asolution of 41 mg of the resultant compound of example 40a and 45 mgN,N-diisopropylethylamine in CH₂ Cl₂. The mixture was stirred for 4 h,diluted with CH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl,then dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas subjected to preparative HPLC to yield 18 mg of the title product.TLC: Rf=0.83 (5:10:85 NH₄ H/CH₃ OH/CH₂ Cl₂). HPLC: Rt=15.78 min. (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 165

Compound 165

A solution of 36 mg of the resultant compound of Example 51D in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 20 mg ofp-toluenesulfonyl chloride and 18 mg of sodium bicarbonate. The mixturewas stirred for 3 h, diluted with CH₂ Cl₂, washed with saturated NaClthen dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by low pressure silica gel chromatography using 5 diethylether/CH₂ Cl₂ as eluent to provide 38 mg of the title product as a whitesolid. TLC: Rf=0.15, 5% diethyl ether/CH₂ Cl₂. HPLC: Rt=15.27 min. (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 166

A. Compound XXII (P=tert-butoxycarbonyl, D'=cyclopentylmethyl,E=4-methoxyphenyl)

To a solution of the resultant compound of Example 114B (1.8 g, 4.96mmol) in CH₂ Cl₂ (10 mL) was added 4-methoxylbenzensulfonyl chloride(2.10 g, 9.93 mmol), followed by addition of a saturated solution ofsodium bicarbonate (3 mL) and 0.83 g of solid sodium bicarbonate. Themixture was stirred at ambient temperature for 24 hours. The solutionwas diluted with 200 mL CH₂ Cl₂, the organics were separated, dried overanhydrous MgSO₄, and concentrated under reduced pressure. The crudeproduct was purified via medium pressure liquid chromatography using CH₂Cl₂, followed by 1:99 methanol/CH₂ Cl₂ followed by 2:98 methanol/CH₂ Cl₂as the solvent system to give 1.49 g of the title compound as a whitesolid. TLC: Rf=0.37, 3:97 methanol/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃)consistent with structure.

B. Compound XXII (P=H, D'=cyclopentylmethyl, E=4-hydroxyphenyl)

A solution of the resultant compound of Example 166A (1.11 g, 2.08 mmol)in CH₂ Cl₂ (20 mL) was added to a solution of boron tribromide in CH₂Cl₂ (1.0M, 10.4 mL). The mixture was stirred at ambient temperature for24 hours. The solution was poured onto 40 mL of a saturated solution ofsodium bicarbonate. The aqueous layer was extracted with 250 mL CH₂ Cl₂followed by extraction with 250 mL EtOAc. The combined organics weredried over anhydrous MgSO₄, concentrated under reduced pressure and thecrude product purified via medium pressure column chromatography using agradient solvent system of CH₂ Cl₂, followed by 1:99 methanol/CH₂ Cl₂,followed by 9:98 methanol/CH₂ Cl₂, followed by a 1:5:95 concentrated NH₄OH/methanol/CH₂ Cl₂ solution as the solvent system to give 0.38 g of thetitle compound. TLC: Rf=0.18, 3:97 methanol/CH₂ Cl₂, (¹ H)-NMR (CDCl₃)consistent with structure.

C. Compound 166

To a solution of the resultant compound of Example 166B (300 mg, 0.69mmol) in CH₂ Cl₂ (5 mL) was added triethylamine (0.12 mL, 8.6 mmol),followed by slow addition over 3 hours of the resultant compound ofExample 82A (0.21 g, 0.77 mmol) as a solution in CH₂ Cl₂ (5 mL). Themixture was stirred at ambient temperature for 24 hours. The solutionwas diluted with 250 mL CH₂ Cl₂, washed with water, dried over anhydrousMgSO₄, and the organics concentrated under reduced pressure. The crudeproduct was purified via medium pressure column chromatography using agradient solvent system of CH₂ Cl₂ followed by 1:99 methanol/CH₂ Cl₂,followed by 2:98 methanol/CH₂ Cl₂ as the solvent system to give 110 mgof a white solid. TLC: Rf=0.14 (3:97 methanol/CH₂ Cl₂), HPLC: Rt=12.69min, (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 167

Compound 167

A solution of 102 mg of the resultant compound of Example 51D in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 65 mg ofp-nitrobenzenesulfonyl chloride and 51 mg of sodium bicarbonate. Themixture was stirred for 14 h, diluted with CH₂ Cl₂, washed withsaturated NaCl, then dried over MgSO₄, filtered, and concentrated invacuo. The residue was purified by low pressure silica gelchromatography using 20% diethyl ether/CH₂ Cl₂ as eluent to provide 124mg of the title product as a white solid. TLC: Rf=0.36, 20% diethylether/CH₂ Cl₂. HPLC: Rt=15.15 min. (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 168

Compound 168

A solution of 124 mg of the resultant compound of Example 167 in ethylacetate was treated, at ambient temperature, with 13 mg of 10% palladiumon carbon. The mixture was stirred for 14 h under an atmosphere ofhydrogen, filtered through a pad of Celite filter agent, andconcentrated in vacuo. The residue was subjected to preparative HPLC toyield 82 mg of the title product as a white solid. TLC: Rf=0.10, 20%ether/CH₂ Cl₂. HPLC: Rt=13.16 min. (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 169

Compound 169

To a solution of the resultant compound of Example 166B (80 mg, 0.18mmol) in CH₂ Cl₂ (15 mL) was added a saturated solution of sodiumbicarbonate (5 mL) followed by the addition of the resultant compound ofExample 48A (55 mg, 0.24 mmol). The mixture was stirred at ambienttemperature for 5 hours. The solution was diluted with 200 mL CH₂ Cl₂,the organics separated, dried over anhydrous MgSO₄, and concentratedunder reduced pressure. The crude product was purified via mediumpressure liquid chromatography using CH₂ Cl₂, followed by 1:99methanol/CH₂ Cl₂ as the solvent system to give 56 mg of the titlecompound as a white solid. TLC: Rf=0.24, 3:97 methanol/CH₂ Cl₂, HPLC:Rt=14.29 min. (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 170

A. Compound XXII (A=tert-butoxycarbonyl, D'=cyclopentylmethyl,E=4,nitrophenyl)

To a solution of the resultant compound of Example 114B (250 mg, 0.69mmol) in CH₂ Cl₂ (15 mL) was added a saturated solution of sodiumbicarbonate (5 mL) followed by solid sodium bicarbonate (0.12 g, 1.37mmol) and 4-nitrobenzensulfonyl chloride (200 mg, 0.9 mmol). The mixturewas stirred at ambient temperature for 24 hours. The solution wasdiluted with 200 mL CH₂ Cl₂, the organics separated, dried overanhydrous MgSO₄, and concentrated under reduced pressure. The crudeproduct was purified via medium pressure liquid chromatography using agradient solvent system of CH₂ Cl₂ followed by 1:99 methanol/CH₂ Cl₂ togive 360 mg of the title compound as an orange solid. TLC: Rf=0.45, 3:97methanol/CH₂ Cl₂. (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound XXII (A=H, D'=cyclopentylmethyl, E-4-nitrophenyl,hydrochloride salt)

To the resultant compound of Example 170A (360 mg, 0.66 mmol) was added10% w/w HCl in EtOAc (15 mL). The mixture was stirred for 3 hours atambient temperature. The solution was concentrated under reducedpressure to give 310 mg of the title compound as an orange solid whichwas used directly for subsequent reaction. TLC: Rf=0.70, 1:10:90 NH₄OH/methanol/CH₂ Cl₂.

C. Compound 170

To a solution of the resultant compound of Example 170B (310 mg, 0.64mmol) in CH₂ Cl₂ (15 mL) was added a saturated solution of sodiumbicarbonate (5 mL) followed by the addition of solid sodium bicarbonate(0.11 g, 1.3 mmol) and the resultant compound of Example 48A (0.18 g,0.77 mmol). The mixture was stirred at ambient temperature for 24 hours.The solution was diluted with 150 mL CH₂ Cl₂, the organics separated,dried over anhydrous MgSO₄, and concentrated under reduced pressure. Thecrude product was purified via medium pressure liquid chromatographyusing CH₂ Cl₂, followed by 1:99 methanol/CH₂ Cl₂ as the solvent systemto give 0.32 g of the title compound as a white solid. TLC: Rf=0.28,3:97 methanol/CH₂ Cl₂, HPLC: Rt=16.06 min, (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 171

Compound 171

A solution of the resultant compound of Example 170C (0.19 g, 0.34 mmol)in EtOAc (10 mL) was treated at ambient temperature with 50 mg of 10%palladium on carbon and hydrogenated for 72 hours under a slightpositive pressure of hydrogen. The mixture was filtered and concentratedin vacuo and the crude product purified via medium pressure liquidchromatography using CH₂ Cl₂, followed by 1:99 methanol/CH₂ Cl₂,followed by 3:97 methanol/CH₂ Cl₂, followed by 10:90 methanol/CH₂ Cl₂ asthe solvent system to give 97 mg of the title compound as a white solid.TLC: Rf=0.25, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=14.28 min, (¹ H)-NMR(CDCl₃) consistent with structure.

EXAMPLE 172

A. Compound XXII (A=tert-butoxycarbonyl, D'=cyclopentylmethyl,E=2,4-dinitrophenyl)

To a solution of the resultant compound of Example 114B (500 mg, 1.38mmol) in CH₂ Cl₂ (15 mL) was added a saturated solution of sodiumbicarbonate (5 mL) followed by solid sodium bicarbonate (0.23 g, 2.76mmol) and 2,4-dinitrobenzenesulfonyl chloride (440 mg, 1.65 mmol). Themixture was stirred at ambient temperature for 2 hours. The solution wasdiluted with 200 mL CH₂ Cl₂, the organics separated, dried overanhydrous MgSO₄, and concentrated under reduced pressure. The crudeproduct was purified via medium pressure liquid chromatography using agradient solvent system of CH₂ Cl₂, followed by 1:99 methanol/CH₂ Cl₂ togive 700 mg of the title compound as a brown solid. TLC: Rf=0.48, 3:97methanol/CH₂ Cl₂, (¹ H)-NMR (CDCl₃), consistent with structure.

B. Compound XXII (A=H, D'=cyclopentylmethyl, E-2,4-dinitrophenyl,hydrochloride salt)

To a the resultant compound of Example 172A (700 mg, 1.18 mmol) wasadded 10% w/w HCl in EtOAc (20 mL). The mixture was stirred for 3 hoursat ambient temperature. The solution was concentrated under reducedpressure to give 590 mg of the title compound as a brown solid which wasused without subsequent purification. TLC: Rf=0.55, 1:10:90 NH₄OH/methanol/CH₂ Cl₂.

C. Compound 172

To a solution of the resultant compound of 172B (590 mg, 1.11 mmol) inCH₂ Cl₂ (15 mL) was added a saturated solution of sodium bicarbonate (5mL), followed by solid sodium bicarbonate (0.19 g, 2.2 mmol) and theresultant compound of Example 48A (0.31 g, 1.3 mmol). The mixture wasstirred at ambient temperature for 24 hours. The solution was dilutedwith 150 mL CH₂ Cl₂, the organics separated, dried over anhydrous MgSO₄,and the organics concentrated under reduced pressure. The crude productwas purified via medium pressure liquid chromatography using a CH₃OH/CH₂ Cl₂ gradient as eluant, to yield the product as 0.59 g of a whitesolid. HPLC: Rt=16.36 min, (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 173

Compound 173

A solution of the resultant compound of Example 172C (0.20 g, 0.33 mmol)in EtOAc (10 mL) was treated under ambient temperature with 50 mg of 10%palladium on carbon and hydrogenated for 72 hours under a slightpositive pressure of hydrogen. The mixture was filtered and concentratedin vacuo and the crude product purified via medium pressure liquidchromatography using CH₂ Cl₂, followed by 1:99 methanol/CH₂ Cl₂, 3:97methanol/CH₂ Cl₂, and 10:90 methanol/CH₂ Cl₂ as the solvent system togive 120.2 mg of the title compound as a light brown solid. TLC:Rf=0.17, 3:97 methanol/CH₂ Cl₂, HPLC: Rt=13.47 min, (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 174

A. 4-Benzyloxybenzenesulfonyl chloride

To 0.87 g of dimethylformamide, at 0° C. under an atmosphere ofnitrogen, was added 1.61 g of sulfuryl chloride. The mixture was stirredfor 15 min and treated with 2.00 g of benzyl phenyl ether. The mixturewas then heated at 100° C. for 1.5 h, cooled to about 40° C., pouredonto ice, extracted with CH₂ Cl₂, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by low pressure silicagel chromatography using 10% ethyl acetate in hexane as eluent toprovide 0.78 g of the title product as a white solid. TLC: Rf=0.46, 10%ethyl acetate in hexane. (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound 174

A solution of 30 mg of the resultant compound of Example 51D in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 24 mg of the resultantcompound of Example 174A and 18 mg of sodium bicarbonate. The mixturewas stirred for 14 h, diluted with CH₂ Cl₂, washed with saturated NaClthen dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by low pressure silica gel chromatography using 20% diethylether/CH₂ Cl₂ as the eluent to provide 14 mg of the title product as awhite solid. TLC: Rf=0.43, 20% diethyl ether/CH₂ Cl₂. HPLC: Rt=17.01min. (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 175

Compound 175

A solution of 11 mg of the resultant compound Example 174B in ethylacetate was treated at ambient temperature, with 2 mg of 10% palladiumon carbon. The mixture was stirred for 14 h under an atmosphere ofhydrogen, filtered through a pad of Celite filter agent, filtered, andconcentrated in vacuo. The residue was purified by low pressure silicagel chromatography using 10% methanol in CH₂ Cl₂ as the eluent toprovide 9 mg of the title product as a white solid. TLC: Rf=0.38, 10%methanol in CH₂ Cl₂. HPLC: Rt=13.37 min. (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 176

A. 1,3-Benzodioxole-5-sulfonyl chloride

To 3.50 g of dimethylformamide, at 0° C. under an atmosphere ofnitrogen, was added 6.47 g of sulfuryl chloride. The mixture was stirred15 min and treated with 5.32 g of 1,3-benxodioxole. The mixture was thenheated at 120° C. for 45 min, cooled to about 40° C., poured onto ice,extracted with CH₂ Cl₂, dried over MgSO₄, filtered, and concentrated invacuo. The residue was purified by low pressure silica gelchromatography using 40% CH₂ Cl₂ in hexane as eluent to provide 2.70 gof the title product as a yellow solid. TLC: Rf=0.37, 40% CH₂ Cl₂ inhexane. (¹ H)-NMR (CDCl₃) consistent with structure. ps B. Compound XXII(A=tert-butoxy, D'=isobutyl, E=3,4-benzodioxole)

A solution of 49 mg of the resultant compound of Example 39A in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 45 mg of the resultantcompound of Example 176A and 28 mg of sodium bicarbonate. The mixturewas stirred for 14 h, diluted with CH₂ Cl₂, washed with saturated NaClthen dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by low pressure silica gel chromatography using 20% diethylether/CH₂ Cl₂ as the eluent to provide 71 mg of the title product as awaxy solid. TLC: Rf=0.65, 20% diethyl ether/CH₂ Cl₂. (¹ H)-NMR (CDCl₃)consistent with structure.

C. Compound XXII (A=H, D'=isobutyl, E=3,4-benzodioxole, hydrochloridesalt)

A solution of 71 mg of the resultant compound of Example 176B in ethylacetate was treated at -20 ° C. with HCl gas. The HCl was bubbledthrough the mixture for 20 min over which time the temperature wasallowed to warm to 20° C. Nitrogen was then bubbled through the mixturefor 15 min and solvent removed in vacuo to yield 66 mg of the titleproduct as a white solid which was used directly in subsequentreactions.

D. Compound 176

A solution of 18 mg of the resultant compound of Example 176C in CH₂ Cl₂was added, at ambient temperature under an atmosphere of nitrogen, to asolution of 13 mg of the resultant compound of Example 48A and 14 mgN,N-diisopropylethylamine in CH₂ Cl₂. The mixture was stirred for 16 h,diluted with CH₂ Cl₂, washed with saturated NaHCO₃ and saturated NaCl,then dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by low pressure silica gel chromatography using 5% diethylether/CH₂ Cl₂ as the eluent to provide 9 mg of the title product as awhite solid. TLC: Rf=0.14, 5% diethyl ether/CH₂ Cl₂. HPLC: Rt=15.52 min;(¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 177

A. (4-Methoxyphenyl)-methyl-4-nitrophenyl carbonate

To a solution of 1.50 g of p-nitrophenyl chloroformate in 30 mL of CH₂Cl₂ at 0° C. was added sequentially, 0.77 mL of 4-methoxybenzyl alcoholand 0.82 mL of 4-methyl morpholine. After stirring for a half hour atambient temperature, the resulting mixture was diluted with CH₂ Cl₂,washed with water, brine, dried over magnesium sulfate, filtered andconcentrated in vacuo to yield a pale yellow solid which was trituratedwith CH₂ Cl₂ /hexane and filtered to yield 1.51 g of the title compound.TLC: Rf=0.40, 20% EtOAc/hexane.

B. Compound 177

To a solution of 96.7 mg of the resultant compound of Example 141A in 2mL of CH₂ Cl₂ was added sequentially, 90 μL of diisopropylethylamine and81.3 mg of the resultant compound of Example 178A. After stirring for 24hours, the mixture was diluted with CH₂ Cl₂, washed with water andbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by preparative thin layer chromatography using5% methanol in CH₂ Cl₂ eluent to yield 104.8 mg of the title compound.TLC: Rf=0.4, 20% EtOAc/hexane, HPLC: Rt=17.66 min, (¹ H)NMR (CDCl₃)consistent with structure.

EXAMPLE 178

A. (3-Methoxyphenyl)-methyl-4-nitrophenyl carbonate

Prepared by the same route as described for Example 177A, except3-methoxybenzyl alcohol was utilized for reaction with p-nitrophenylchloroformate to yield the title compound as a pale yellow solid. TLC:Rf=0.40, 20% EtOAc/hexane.

B. Compound 178

To a solution of 97.8 mg of the resultant compound of Example 141A in 2mL of CH₂ Cl₂ was added sequentially, 91 μL of disopropylethylamine and82.2 mg of the resultant compound of Example 178A. After stirring for 24hours, the mixture was diluted with CH₂ Cl₂, washed with water andbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by preparative thin layer chromatography using5% methanol in CH₂ Cl₂ eluent to yield 25.7 mg of the title compound.TLC: Rf=0.4, 20% EtOAc/hexane, HPLC: Rt=17.75 min. (¹ H)NMR (CDCl₃)consistent with structure.

EXAMPLE 179

A. (2-Methoxyphenyl)-methyl-4-nitrophenyl carbonate

Prepared by the same route as described for Example 177A, except2-methoxybenzyl alcohol was utilized for reaction with p-nitrophenylchloroformate to yield the title compound as a pale yellow solid. TLC:Rf=0.40, 20% EtOAc/hexane.

B. Compound 179

To a solution of 97.8 mg of the resultant compound of Example 141A in 2mL of CH₂ Cl₂ was added sequentially, 99 μL of diisoprophylethylamineand 89.2 mg of the resultant compound of Example 179A. After stirringfor 24 hours the mixture was diluted with CH₂ Cl₂, washed with water andbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by preparative thin layer chromatography using5% methanol in CH₂ Cl₂ eluent to yield 107.0 mg of the title compound.TLC: Rf=0.4, 20% EtOAc/hexane, HPLC: Rt=17.58 min. (¹ H)NMR (CDCl₃)consistent with structure.

EXAMPLE 180

A. 2,3-Dihydrobenzofuran-5-sulfonyl chloride

To 3.35 g of dimethylformamide, at 0° C. under an atmosphere ofnitrogen, added 6.18 g of sulfuryl chloride. The mixture was stirred 15min and treated with 4.69 g of 2,3-dihydrobenzofuran. The mixture wasthen heated at 100° C. for 1.5 h, cooled to about 40° C., poured ontoice, extracted with CH₂ Cl₂, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was taken up in ethyl acetate, cooledto 5° C. for 16 h, and the resultant pink crystals collected by vacuumfiltration to provide 6.12 g of the title product. TLC: Rf=0.41, 10%ethyl acetate in hexane. (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound 180

A solution of 32 mg of the resultant compound of Example 140D in 4:1 CH₂Cl₂ /saturated aqueous NaHCO₃ was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 22 mg of the resultantcompound of Example 180A and 18 mg of sodium bicarbonate. The mixturewas stirred 14 h, diluted with CH₂ Cl₂, washed with saturated NaCl thendried over MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by low pressure silica gel chromatography using 20% diethylether/CH₂ Cl₂ as eluent to provide 20 mg of the title product as a whitesolid. TLC: Rf=0.52, 20% diethyl ether/CH₂ Cl₂. HPLC: Rt=15.49 min (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 181

Compound 181

A solution of the resultant compound of Example 140D (150 mg, 0.4 mmol)in CH₂ Cl₂ (10 mL) was added a saturated solution of sodium bicarbonate(5 mL) followed by solid sodium bicarbonate (0.1 g, 1.2 mmol) and4-cyanobenzensulfonyl chloride (0.1 g, 0.48 mmol). The mixture wasstirred at ambient temperature for 4 hours. The solution was dilutedwith 200 mL CH₂ Cl₂, the organics separated, dried over anhydrous MgSO₄,and the organics concentrated under reduced pressure. The crude productwas purified via medium pressure liquid chromatography using CH₂ Cl₂,followed by 1:99 methanol/CH₂ Cl₂ solution as the solvent system to give0.19 g (86% yield) of the title compound as a white solid. TLC: Rf=0.40,3:97 methanol/CH₂ Cl₂, HPLC: Rt=15.02 min, (¹ H)-NMR (CDCl₃) consistentwith structure.

EXAMPLE 182

Compound 182

This compound was prepared from the resultant compound of Example 114Dand the resultant compound of Example 48A in the same manner describedin Example 88. After workup and purification by preparativereversed-phase C₁₈ HPLC using a linear gradient of 35% to 100% CH₃ CN/H₂O with 0.1% TFA as eluant, 32.8 mg of the title compound was obtained.TLC: Rf=0.25, 4% MeOH/CH₂ Cl₂. HPLC: Rt=16.06 min; (¹ H)NMR (CDCl₃)consistent with structure.

EXAMPLE 183

Compound 183

This compound was prepared from the resultant compound of Example 84 bytreatment with hydrogen chloride gas and subsequent reaction with theresultant compound of Example 48A in the manner described in Example132. After workup and purification by crystallization from EtOAc, 33.0mg of the title compound was obtained as a white solid. TLC: Rf=0.25, 4%MeOH/CH₂ Cl₂. HPLC: Rt=17.71 min; (¹ H)-NMR (CDCL₃) consistent withstructure.

EXAMPLE 184

A. (N-tert-butoxycarbonyl)-(R)-3-pyrrolidinyl-N-hydroxysuccinimidylcarbonate

To a solution of 1.0 g of (R)-3-hydroxypyrrolidine in tetrahydrofuran(50 mL) was added sequentially, at ambient temperature, 3.75 g ofdi-tert-butyl dicarboante and 1 mL of 2N sodium hydroxide. The mixturewas stirred for 1 hour, filtered and concentrated in vacuo. Theresultant compound was reacted with N,N-disuccinimidyl carbonate in themanner described in Example 155A. Workup and purification by thick layersilica gel chromatography using an EtOAc eluent yielded the titlecompound as a white solid; (¹ H)-NMR (CDCl₃) consistent with structure.

B. Compound 184

A solution of 350 mg of the resultant compound of Example 166A wasdeprotected with hydrogen chloride gas and the resultant compound wasreacted with the resultant compound of Example 184A in the mannerdescribed in Example 88. After concentration of the mixture in vacuo andworkup, the residue was purified by thick layer silica gelchromatography using 7% MeOH/CH₂ Cl₂ as eluant, to obtain 120 mg of thetitle compound. TLC: Rf=0.45, 5% MeOH/CH₂ Cl₂. HPLC: Rt=16.97 min; (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 185

Compound 185

A solution of 120 mg of the resultant compound of Example 184B in EtOAc(25 mL) at 0° C. was treated with anhydrous hydrogen chloride gas for 10min., and allowed to stand for 12 h while warming to ambienttemperature. Concentration in vacuo yielded 110 mg of the titlecompound. TLC: Rf=0.35, 10% MeOH/89% CH₂ Cl₂ /1% NH₄ OH. HPLC: Rt=13.72min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 186

A. Compound XXX ((syn, anti)-OH, A=carbobenzyloxy, R³ =(s)-sec-butyl,R^(3') =H, D'-benzyl, A'=tert-butoxycarbonyl)

A solution of 1.37 g of the resultant compound of Example 1B in 150 mLof methylene chloride was treated with 1.03 g of Cbz-Ile, 523 mg ofHOBT.H₂ O, and 742 mg of EDC. The mixture was stirred for 18 h, thendiluted with 3 volumes of diethyl ether and washed sequentially withwater, saturated NaHCO₃ solution, 10% KHSO₄ solution, and brine. Afterdrying over MgSO₄ and concentrating in vacuo, the residue was purifiedby chromatography on a silica gel column using a gradient of 1% to 1.5%MeOH in CH₂ Cl₂ as eluant to yield 2.10 g of the title compound as awhite foam. TLC: Rf=0.51, 5% methanol/CH₂ Cl₂.

B. Compound XXX ((syn, anti)-OH, A=carbobenzyloxy, R³ =(S)-sec-butyl,R^(3') =H, D'=benzyl, A'=H), hydrochloride salt

A solution of 650 mg of the resultant compound of Example 12A in 12 mLof ethyl acetate was cooled in an ice/water bath and treated with a slowstream of HCl gas for approximately 6 min with vigorous stirring. Themixture was capped and stirred for an additional 10 min, then purgedwith a stream of nitrogen for 15 minutes and concentrated in vacuo toyield a white solid which was used without subsequent purification. TLC:Rf=0.18, 95:5:0.5 CH₂ Cl₂ /methanol/concentrated NH₄ OH.

C. Compound 186

A solution of 20 mg of the resultant compound of Example 186B in 0.8 mLof methylene chloride was cooled in ice/methanol (approximately 15° C.),then treated with 13.8 μL of DIEA followed by 7.6 mg of α-toluenesulfonyl chloride. The mixture was stirred for 15 h, warming slowly toambient temperature. The mixture was concentrated to a small volume,applied to a 0.5 mm thick prep plate and eluted with 3.5% MeOH/CH₂ Cl₂.The band containing the desired diastereomer was isolated and elutedwith 8% MeOH/CH₂ Cl₂ to yield 4.8 mg of the title compound. TLC:Rf=0.42, 15% diethyl ether/CH₂ Cl₂. HPLC: Rt=17.81 min. NMR (CDCl₃):0.78 (dd, 6H) 0.84 (m, 1H) 1.07, (m, 1H) 1.76-1.86 (m, 2H) 2.72 (m, 2H);3.14 (s, 2H); 3.49 (dd, 1H); 3.87 (dd, 1H); 3.58 (m, 1H); 4.01 (d, 1H);4.14, (d, 1H); 4.26, (d, 1H); 4.35, (d, 1H); 4.90, (m, 1H); 5.08, (s,2H); 5.97, (d, 1H), 7.08, (d, 2H); 7.17, (t, 1H); 7.20-7.40, (m, 17H).

EXAMPLE 187

Compound 187

100 mg of the resulting compound 54A was treated with 1 mL of 90%aqueous TFA and allowed to stand for 12 h. The mixture was concentratedin vacuo and the residue taken up in 10 mL of dry CH₂ Cl₂, treated with65 mg of N-Cbz-L-isoleucine (0.235 mmol), 50 μL of DIEA (0.27 mmoles),30 mg of HOBt (0.22 mmoles), and 42 mg of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.22mmoles). The mixture was stirred for 3 h, then diluted with in CH₂ Cl₂and washed sequentially with water, saturated NaHCO₃ solution, andbrine. After drying over MgSO₄ and concentrating in vacuo, the mixturewas purified by chromatography on a silica gel column using 5% CH₃ OH inCH₂ OH in CH₂ Cl₂ as eluent to yield the title compound, a portion whichwas purified by preparative reversed-phase C₁₈ HPLC using a lineargradient of 35% to 100% CH₃ CN/H₂ O with 0.1% TFA for elution to obtain36.0 mg 99.0% pure compound. TLC: Rf=0.25, 5% CH₃ OH in CH₂ Cl₂. HPLC:Rt=16.45 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 188

Compound 188

A solution of 51 mg of the resulting compound of Example 187A in 15 mLof methanol was hydrogenated under a slight positive pressure ofhydrogen in the presence of 10 mg of 10% Pd(OH)₂ for 14 h. Afterfiltering and concentrating in vacuo, the crude mixture was taken upinto 10 mL CH₂ Cl₂ and treated with 0.203 mL of DIEA and 19.0 mg of2-quinoxaloyl chloride. The mixture was stirred for 6 h, then dilutedwith CH₂ Cl₂ and washed with water. After drying over MgSO₄ andconcentrating in vacuo, a portion of the mixture was purified bypreparative reversed-phase C₁₈ HPLC using a linear gradient of 35% to100% CH₃ CN/H₂ O with 0.1% TFA for elution to obtain 2.1 mg of the titlecompound. TLC: Rf=0.25, 6% Ch₃ CN/H₂ O with 0.1% TFA for elution toobtain 2.1 mg of the title compound. TLC: Rf=0.25, 6% CH₃ OH in CH₂ Cl₂.HPLC: Rt=16.21 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 189

A. Compound XXII (D'=isobutyl, A=H, E=4-acetamidophenyl,trifluoroacetate salt)

To a solution of 89.3 mg. (0.167 mmol) of the resultant compound ofExample 39B in CH₂ Cl₂ (1 mL) at 0° to 5° C. was addedtrifluoromethanesulfonic acid (1 mL). After stirring for 0.5 h theresultant mixture was concentrated in vacuo and the resulting yellow gumused without subsequent purification.

B. Compound 189

A solution of the resultant compound of Example 189A (0.167 mmol) in CH₂Cl₂ was treated sequentially, at ambient temperature under an atmosphereof nitrogen, with 44.2 mg (0.217 mmol) of N-Boc-α-aminoisobutyric acid,0.044 mL (0.251 mmol) diisopropylethylamine, 27.1 mg (0.201 mmol) of1-hydroxybenzotriazole hydrate, 38.5 mg (0.201 mmol)1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixturewas stirred for 16 h and then concentrated in vacuo. The residue wastaken up in ethyl acetate and washed with water, 0.5N hydrochloric acid,washed with sodium bicarbonate, saturated brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bylow pressure silica gel column chromatography using a 10% to 35%gradient of ethyl acetate/CH₂ Cl₂ eluent to yield 69.3 mg of the titleproduct as a white solid. TLC: Rf=0.46, 60% ethyl acetate/CH₂ Cl₂, HPLC:Rt=15.0 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 190

A. Compound XXXI (A=H, R³ =methyl, R^(3') =methyl, D'=isobutyl,E=4-acetamidophenyl, hydrochloride salt)

To a solution of 60.1 mg of the resultant compound of Example 189B inCH₂ Cl₂ (1 mL) at 0° to 5° C. was added trifluoromethanesulfonic acid (1mL). After stirring for 0.75 h, the resultant mixture was concentratedin vacuo and the resulting white solid used directly for subsequentreaction.

B. Compound 190

To a solution of 37 mg (0.059 mmol) of the resultant compound of Example190A in CH₂ Cl₂ (3 mL) was added sequentially, at ambient temperatureunder an atmosphere of nitrogen, with 15.4 mg (0.089 mmol) of1-hydroxybenzotriazole hydrate, and 17.8 mg (0.089 mmol) EDC. Themixture was stirred for 16 h and then concentrated in vacuo. The residuewas taken up in EtOAc and washed with saturated brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by thin layer silica gel column chromatography using 50% ofEtOAc in CH₂ Cl₂ as eluent to yield 32.5 mg of the title product. TLC:Rf=0.35, 50% EtOAc/CH₂ Cl₂, HPLC: Rt=15.65 min; (¹ H)-NMR (CDCl₃)consistent with structure.

EXAMPLE 191

A. (2S,3RS)-S-Amino-1-chloro-2-hydroxy-4-phenylbutane)

A solution of 2.24 g (6.71 mmol) of(1S,2RS)-N-(1-benzyl-3-chloro-2-hydroxypropyl)benzyloxycarbonylamine in5 mL of methanol was added, at ambient temperature under a nitrogenatmosphere, to a slurry of 0.22 g (10% by weight) of 10% palladium oncarbon in 60 mL methanol and hydrogenerated for 24 h, under a slightpositive pressure of hydrogen. The mixture was filtered and concentratedin vacuo to yield 1.34 g of the mixed diastereomeric products. TLC:Rf=0.33, 10% CH₃ OH/CH₂ Cl₂.

B. (2S)-2-Benzyloxycarbonylamino-N¹-((1S,2RS)-1-benzyl-3-chloro-2-hydroxypropyl)-N⁴ -trityl succinamide

A solution of 1.34 g (6.71 mmol) of the resultant compounds of Example191A in 60 mL of dichloromethane was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 3.58 g (7.05 mmol) ofCbz-N.sup.δ -trityl-asparagine, 0.95 g (7.05 mmol) of1-hydroxybenzotriazole hydrate, 1.35 g (7.05 mmol) of EDC. The mixturewas stirred for 24 hours and then concentrated in vacuo. The residue wastaken up in ethyl acetate and washed with water, saturated NaHCO₃,saturated NaCl; dried over MgSO₄ ; filtered and concentrated in vacuo.The residue was purified by low pressure silica gel columnchromatography using 10% ethyl acetate/dichloromethane as eluent toyield 3.08 g total of the mixed diastereomeric products. TLC: Rf=0.75,0.83, 40% EtOAc/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistent with structure.

C. (2S)-2-Amino-N¹ -((1S,2RS)-1-benzyl-3-chloro-2-hydroxypropyl)-N⁴-trityl succinamide

A solution of 2.80 g (4.06 mmol) of the resultant compounds of Example191B in 5 mL of methanol was added, at ambient temperature under anitrogen atmosphere, to a slurry of 0.28 g (10% by weight) of 10%palladium on carbon in 100 mL methanol and hydrogenated for 24 h under aslight positive pressure of hydrogen. The mixture was filtered andconcentrated in vacuo to yield 2.26 g of the mixed distereomericproducts. TLC: Rf=0.42, 10% CH₃ OH/CH₂ Cl₂.

D. (2S)-2-((1S,2RS)-1-Benzyl-3-chloro-2-hydroxypropyl)-N¹-((quinoline-2-carbonyl)-amino)-N⁴ -trityl succinamide

A solution of 2.26 g (4.06 mmol) of the resultant compounds of Example191C in 60 mL of dichloromethane was treated sequentially, at ambienttemperature under an atmosphere of nitrogen, with 0.74 g (4.27 mmol) ofquinaldic acid, 0.58 g (4.27 mmol) of 1-hydroxybenzotriazole hydrate,and 0.82 g (4.27 mmol) of EDC. After 24 hours, 30 mL of dichloromethanewas added. The mixture was washed with water, 5% NaHCO₃ solution,saturated NaCl, dried over MgSO₄, filtered and concentrated in vacuo.The residue was dissolved in 50% ethyl acetate/hexane and filteredthrough a plug of silica gel. Removal of the solvents yielded 2.30 g ofthe mixed diastereomeric products. TLC: Rf=0.53, 0.58, 40% EtOAc/CH₂ Cl₂; (¹ H)-NMR (CDCl₃) consistent with structure.

E. (2S)-2-((1S,2RS)-1-Benzyl-2-hydroxy-3-iodopropyl)N¹-((quinoline-2-carbonyl)-amino)-N⁴ -trityl succinamide

A solution of 1.05 g (1.48 mmol) of the resultant compounds of Example191D and 0.36 g (2.37 mmol) of sodium iodide in 15 mL of methyl ethylketone was heated to reflux for 24 hours. The mixture was cooled to roomtemperature and then concentrated in vacuo. The residue was taken up indichloromethane and washed with water, saturated NaCl, dried over MgSO₄,filtered and concentrated in vacuo to yield 1.3 g of the mixeddiastereomeric products. TLC: Rf=0.58, 0.65, 40% EtOAc/CH₂ Cl₂ ; (¹H)-NMR (CDCl₃) consistent with structure.

F. (2S)-2-((1S,2 syn,anti)-3-(2-methylpropyl)amino-1-benzyl-2-hydroxypropyl)-N¹-((quinoline-2-carbonyl)-amino)-N⁴ -trityl succinamide

A solution of 207.6 mg (0.26 mmol) of the resultant compounds of Example191E and 0.5 mL (5.17 mmol) of isobutylamine in 9 mL of acetonitrile ina sealed tube was heated to reflux for 24 hours. After cooling to roomtemperature, the mixture was concentrated in vacuo. The residue wastaken up in dichloromethane and washed with water, saturated NaCl, driedover MgSO₄, filtered and concentrated in vacuo to yield 209.2 mg of themixed diastereomeric products. TLC: Rf=0.11, 10% CH₃ OH/CH₂ Cl₂ ; (¹H)-NMR (CDCl₃) consistent with structure.

G. Compound XIV ((syn, anti)-OH, P=quinoline-2-carbonyl, D'=isobutyl)

A solution of 192.9 mg (0.26 mmol) of the resultant compounds of Example191F and 0.07 mL (0.388 mmol) of diisopropylethylamine in 5 mL ofdichloromethane was treated with 112.9 mg (0.517 mmol) ofdi-tert-butyldicarbonate. After 24 hours, the mixture was diluted withdichloromethane. The mixture washed with water, 5% NaHCO₃, 0.5N HCl,saturated NaCl, dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by low pressure silica gel columnchromatography using 40% ethyl acetate/dichloromethane as eluent toyield 147.3 mg of the mixed diastereomeric products. TLC: Rf=0.60, 0.67,40% EtOAc/CH₂ Cl₂ ; (¹ H)-NMR (CDCl₃) consistent with structure.

H. Compounds 191

A solution of 147.3 mg (0.174 mmol) of the resultant compounds ofExample 191G in 2 mL of dichloromethane was treated with 2 mL oftrifluoroacetic acid. After 4 hours, the mixture was concentrated invacuo. TLC: Rf=0.11, 10% CH₃ OH/CH₂ Cl₂. To a solution of the resultantcompound in 2 mL of dichloromethane was sequentially added 0.5 mL ofsaturated NaHCO₃, small amount of solid NaHCO₃ and 67 mg (0.226 mmol) ofa mixture of 4-acetamido-3-fluorobenzenesulphonyl chloride and3-acetamido-4-fluorobenzenesulphonyl chloride. After 3 hours, themixture was diluted with dichloromethane. The two layers were separatedand the aqueous layer was extracted once with dichloromethane. Thecombined organic layer was washed with saturated NaCl then dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified bylow pressure silica gel column chromatography using 2%methanol/dichloromethane was eluent to yield 64 mg of the mixeddiastereomers and regioisomers which were further purified withpreparative HPLC to yield 18.9 mg of the mixed regioisomers comprisingcompounds 191 as a white solid. TLC: Rf=0.14, 5% CH₃ OH/CH₂ Cl₂ ; HPLC,Rt=13.36 min; (¹ H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 193

Compound 193

A solution of 81.2 mg (0.096 mmol) of the resultant lower Rfdiastereomer of Example 9/192A in 3 mL of dichloromethane was treatedwith 3 mL of trifluoroacetic acid. After 4 hours, the mixture wasconcentrated in vacuo. TLC: Rf=0.11, 10% CH₃ OH/CH₂ Cl₂. To a solutionof 20.6 mg (0.0431 mmol) of the resultant residue in 1 mL ofdichloromethane was sequentially added 0.3 mL of saturated NaHCO₃, smallamount of solid NaHCO₃ and 12.4 mg (0.053 mmol) of4-acetamidobenzenesulphonyl chloride. After 3 hours, the mixture wasdiluted with dichloromethane. The two layers were separated and theaqueous layer was extracted once with dichloromethane. The combinedorganic layer was washed with brine then dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by preparative HPLC toyield 8.3 mg of the title compound as a white solid; TLC: Rf=0.10, 5%CH₃ OH/CH₂ Cl₂ ; HPLC, Rt=12.7 min; (¹ H)-NMR (CDCl₃) consistent withstructure.

EXAMPLE 194

Compound 194

To a solution of 13.0 mg (0.026 mmol) of the trifluoroacetic aciddeprotection product described in Example 193 in 1 mL of dichloromethanewas sequentially added 0.3 mL of saturated NaHCO₃, small amount of solidNaHCO₃ and 8.4 mg (0.033 mmol) of 5-(isoxazol-3-yl)thiophene-2-sulphonylchloride. After 3 hours, the mixture was diluted with dichloromethane.The two layers were separated and the aqueous layer was extracted oncewith dichloromethane. The combined organic layer was washed with brinethen dried over MgSO₄, filtered and concentrated in vacuo. The residuewas purified by preparative HPLC to yield 5.1 mg of the title product asa white solid; TLC: Rf=0.27, 5% CH₃ OH/CH₂ Cl₂ ; HPLC, Rt=14.4 min; (¹H)-NMR (CDCl₃) consistent with structure.

EXAMPLE 195

A. Compound XXII(A=(S)-3-tetrahydrofuryl, D'=cyclopentylmethyl,A'=tert-butoxycarbonyl)

To a solution of 264 mg of the resultant compound of Example 140D in 10mL of CH₂ Cl₂ was added 0.14 mL of disopropylethylamine and 175 mg ofdi-tert butylpyrocarbonate. After stirring for 4 hours, the mixture wasdiluted with 50 mL of CH₂ Cl₂, washed with 0.5N of HCl and brine, driedover magnesium sulfate, filtered and concentrated in vacuo to yield 364mg of the title compound as a white solid which was used withoutsubsequent purification. TLC: Rf=0.58, 40% EtOAc/CH₂ Cl₂.

B

A solution of 334 mg of the resultant compound of Example 195A in 5 mLof ethanol was hydrogenated under 30 psi of hydrogen in the presence of80 mg of platinum (IV) oxide for 24 hours. The mixture was filtered andconcentrated. The residue was purified by a low pressure silica gelcolumn chromatography using 20% EtOAc in CH₂ Cl₂ eluent to yield 268 mgof the title compound. TLC: Rf=0.55, 40% EtOAc/CH₂ Cl₂. (¹ H)-NMR(CDCl₃) consistent with structure.

C

A solution of 268 mg of the resultant compound of Example 195B in 10 mLof EtOAc was treated with anhydrous HCl gas for 5 min. The reactionmixture was sparged with nitrogen then concentrated in vacuo and theresulting white solid used without subsequent purification forsubsequent reaction.

D. Compound 195

To a solution of 233 mg of the crude resultant compound of Example 195Cin 10 mL of CH₂ Cl₂ was added 2 mL of saturated aqueous sodiumbicarbonate and 149 mg of 4-methyloxybenzene sulfonyl chloride. After 3hours, the resulting mixture was diluted with CH₂ Cl₂, washed withsodium bicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by low pressure silicagel column chromatography using 0% to 20% EtOAc/CH₂ Cl₂ to yield 225 mgof the title compound as a white solid. TLC: Rf=0.40, 20% EtOAc/CH₂ Cl₂; HPLC: Rt=15.65 min.: (¹ H)NMR (CDCl₃) consistent with structure.

EXAMPLE 196

A. (1S,2S)-N-(1-Isobutyl-3-chloro-2-hydroxypropyl)benzyloxycarbonylamine

To a solution of N-Cbz-leucine chloromethyl ketone (2.0 g) in 20 mL ofmethanol was added, at 0° C., 1.0 g of sodium borohydride and themixture was stirred at ambient temperature for 24 h. The solution wasconcentrated under reduced pressure and the residue partitioned between20 mL of saturated aqueous NH₄ Cl and 500 ml of diethyl ether. Theorganic fraction was separated, dried over MgSO₄ and concentrated invacuo and the residue purified by silica gel chromatography to yield 1.8g of white solid.

B. (1S)-1-1(S)(Carbobenzyloxy)amino-2-isobutyloxirane

To a solution of the resultant compound of Example 196A (300 mg) inabsolute ethanol was added 67 mg of powdered KOH. The mixture wasstirred for 3 h at ambient temperature, filtered through diatomaceousearth, and concentrated in vacuo. The residue was dissolved in diethylether, dried over MgSO₄, and concentrated to yield 230 mg of colorlessoil, which was used directly for subsequent reaction.

C. (2R,3S)-N³ -Carbobenzyloxy-N¹-isobutyl-1,3-diamino-2-hydroxy-5-methylhexane

A 230 mg portion of the resultant compound of example 196B was suspendedin 5 mL of isobutylamine and the mixture stirred overnight at ambienttemperature. The mixture was concentrated in vacuo to yield the titleproduct as 179 mg of a white solid, which was used directly forsubsequent reaction.

D. Compound I (A=tert-butoxycarbonyl, x=0,D=isobutyl, E=4-methoxyphenyl,(s)-hydroxy)

Following the procedure described in Example 81, a solution of theresultant compound of example 196C (170 mg) in CH₂ Cl₂ was reacted with4-methoxybenzenxulfoyl chloride (150 mg) in the presence of aqueousNaHCO₃. Workup and silica gel chromatography yielded 90 mg of product asa white solid.

E. Compound I (A=H, x=0, D=isobutyl, E=4-methoxyphenyl, (S)-hydroxy)

A solution of the resultant compound of Example 196D (90 mg) in ethanolwas treated with 50 mg of 10% palladium on carbon and the mixturestirred under an atmosphere of hydrogen. After completion of reaction,the mixture was filtered and concentrated in vacuo to yield 60 mg of thetitle compound which was used directly for subsequent reaction.

F. Compound 196

Reaction of the resultant compound of Example 196E (60 mg) in CH₂ Cl₂was reacted with the resultant product of example 48A (150 mg) asdescribed earlier yielded, following aqueous workup, drying over MgSO₄,filtering, and concentration in vacuo, a residue which was purified bysilica gel chromatography using methanol/CH₂ CL₂ as eluant to yield thetitle product as 40 mg of white solid. ¹ h!-NMR(CDCl₃) consistent withstructure.

EXAMPLE 197

We measured the inhibition constants of the compounds listed in TableVII against HIV-1 protease using the above-cited method of Pennington etal.

We also measured the anti-viral potency of the compounds in CCRM-CEMcells by the above-cited method of Meek et al. In the Tables below,K_(i) and IC₉₀ values are expressed in nM.

In Table VIII, the following classifications have been employed:

A: inhibits HIV replication at concentration of 100 nM or less.

B: inhibits HIV replication at concentration of between 101 and 1,000nM.

C: inhibits HIV replication at a concentration of between 1,001 and10,000 nM.

D: inhibits HIV replication at a concentration of between 10,001 and40,000 nM.

ND: not tested.

                  TABLE VII                                                       ______________________________________                                        Com-             Com-            Com-                                         pound  K.sub.i value                                                                           pound   K.sub.i value                                                                         pound K.sub.i value                          ______________________________________                                        1      4.0       55      430     109   6.0                                    2      2.0       56      60      110   28                                     3      32        57      200                                                  4      19        58      34      111   0.3                                    5      2.0       59      206     112   4.0                                    6      3.0       60      4.0     113   3.0                                    7      8.0                       114   0.35                                   8      850       61      4.0     115   0.5                                    9      4.0       62      72      116   <0.1                                   10     4.0       63      7.0     117   0.26                                                    64      3.0     118   <0.1                                   11     34        65      0.7     119   1.8                                    12     0.1       66      0.4     120   11                                     13     0.2       67      7,400                                                14     0.1       68      120     121   2.0                                    15     <0.1      69      42      122   1.2                                    16     <0.1      70      25      123   10                                     17     <0.1                      124   1.1                                    18     <0.1      71      470     125   0.3                                    19     <0.1      72      4000    126   310                                    20     0.1       73      140     127   650                                                     74      11      128   >5000                                  21     0.7       75      290     129   19                                     22     1.0       76      ND      130   14                                     23     1.5       77      ND                                                   24     32,500    78      ND      131   60                                     25     3,000     79      ND      132   6.0                                    26     0.1       80      ND      133   24                                     27     8.0                       134   8.4                                    28     17        81      2.3     135   2.7                                    29     17        82      1.5     136   18                                     30     61        83      ND      137   26                                                      84      1.4     138   1.4                                    31     ND        85      4.0     139   1.2                                    32     2.5       86      5.0     140   <0.1                                   33     80        87      10                                                   34     17        88      1.4     141   0.1                                    35     4.0       89      2.0     142   <0.1                                   36     19        90      93      143   <0.1                                   37     0.1                       144   8.0                                    38     1.5       91      2.5     145   1.4                                    39     17        92      20      146   2.0                                    40     1,100     93      0.8     147   1.6                                                     94      1.7     148   0.2                                    41     220       95      1.3     149   1.7                                    42     46        96      8.0     150   6.0                                    43     4,200     97      2.5                                                  44     5.0       98      0.5     151   0.8                                    45     6.0       99      0.24    152   2.5                                    46     154       100     0.16    153   0.2                                    47     4.0                       154   0.5                                    48     1.4       101     250     155   1.7                                    49     9.0       102     33      156   2.8                                    50     11        103     4.5     157   0.7                                                     104     5.5     158   <0.1                                   51     ND        105     7.5     159   0.2                                    52     0.4       106     1.4     160   1.0                                    53     27        107     1.4                                                  54     22        108     2.0     161   20                                     162    0.5                                                                    163    0.5                                                                    164    130                                                                    165    0.4                                                                    166    <0.1                                                                   167    0.45                                                                   168    0.6                                                                    169    <0.1                                                                   170    0.2                                                                    171    0.2                                                                    172    21                                                                     173    0.6                                                                    174    10                                                                     175    0.1                                                                    176    <0.1                                                                   177    <0.1                                                                   178    0.1                                                                    179    0.4                                                                    180    <0.1                                                                   181    0.3                                                                    182    0.2                                                                    183    0.1                                                                    184    5.0                                                                    185    3.5                                                                    186    140                                                                    187    0.3                                                                    188    11.5                                                                   189    5,500                                                                  190    ND                                                                     191    33                                                                     192    67                                                                     193    400                                                                    194    350                                                                    195    0.2                                                                    196    ND                                                                     1001   220                                                                    1002   28                                                                     1003   8                                                                      1004   0.2                                                                    1005   250                                                                    1006   8                                                                      1007   42                                                                     1008   20                                                                     1009   20                                                                     1010   4                                                                      1011   1500                                                                   1012   11                                                                     1013   1500                                                                   1014   9300                                                                   1015   19                                                                     ______________________________________                                    

                  TABLE VIII                                                      ______________________________________                                        Compound  IC.sub.90 Range                                                                           Compound  IC.sub.90 Range                               ______________________________________                                        1         C           55        ND                                            2         B           56        ND                                            3         C           57        ND                                            4         C           58        ND                                            5         B           59        ND                                            6         B           60        C                                             7         D                                                                   8         ND          61        C                                             9         B           62        ND                                            10        B           63        C                                             11        ND          64        C                                             12        A           65        C                                             13        A           66        B                                             14        A           67        ND                                            15        A           68        ND                                            16        B           69        ND                                            17        B           70        ND                                            18        B                                                                   19        B           71        ND                                            20        A           72        ND                                            21        A           73        ND                                            22        B           74        ND                                            23        B           75        ND                                            24        ND          76        ND                                            25        ND          77        ND                                            26        B           78        ND                                            27        C           79        ND                                            28        ND          80        ND                                            29        C                                                                   30        ND          81        C                                             31        ND          82        C                                             32        C           83        ND                                            33        ND          84        C                                             34        ND          85        C                                             35        B           86        B                                             36        ND          87        C                                             37        B           88        B                                             38        C           89        C                                             39        C           90        ND                                            40        ND                                                                                        91        B                                             41        ND          92        ND                                            42        ND          93        B                                             43        ND          94        B                                             44        B           95        C                                             45        C           96        ND                                            46        ND          97        B                                             47        C           98        B                                             48        B           99        B                                             49        C           100       A                                             50        C                                                                                         101       ND                                            51        C           102       ND                                            52        B           103       C                                             53        ND          104       C                                             54        C           105       ND                                                                  106       C                                                                   107       C                                                                   108       C                                             109       B           163       B                                             110       ND          164       ND                                                                  165       B                                             111       C           166       A                                             112       B           167       B                                             113       B           168       A                                             114       B           169       A                                             115       B           170       B                                             116       A                                                                   117       C           171       A                                             118       B           172       ND                                            119       C           173       A                                             120       ND          174       ND                                                                  175       A                                             121       C           176       ND                                            122       C           177       ND                                            123       ND          178       ND                                            124       D           179       ND                                            125       B           180       ND                                            126       ND                                                                  127       ND          181       ND                                            128       ND          182       B                                             129       ND          183       B                                             130       ND          184       ND                                                                  185       ND                                            131       ND          186       ND                                            132       ND          187       B                                             133       ND          188       C                                             134       ND          189       ND                                            135       C           190       ND                                            136       ND                                                                  137       ND          191       C                                             138       B           192       C                                             139       B           193       ND                                            140       A           194       ND                                                                  195       A                                             141       B           196       ND                                            142       A           1001      ND                                            143       A           1002      ND                                            144       B           1003      B                                             145       B           1004      A                                             146       B           1005      ND                                            147       B           1006      ND                                            148       A           1007      ND                                            149       B           1008      ND                                            150       B           1009      ND                                                                  1010      ND                                            151       C           1011      ND                                            152       ND          1012      ND                                            153       ND          1013      ND                                            154       ND          1014      ND                                            155       B           1015      A                                             156       B                                                                   157       B                                                                   158       A                                                                   159       B                                                                   160       A                                                                   161       ND                                                                  162       C                                                                   ______________________________________                                    

As demonstrated in Tables VII and VIII, all of the compounds testeddisplayed inhibitory and anti-viral activity. Moreover, several of thesecompounds exhibited activity levels far greater than those of known HIVprotease inhibitors.

While we have described a number of embodiments of this invention, it isapparent that our basic constructions may be altered to provide otherembodiments which utilize the products and processes of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims, rather than by the specificembodiments which have been presented by way of example.

We claim:
 1. A compound of formula I: ##STR654## wherein: A is selectedfrom the group consisting of H; Ht; --R¹ --Ht; --R¹ --C₁ -C₆ alkyl,which is optionally substituted with one to two groups independentlyselected from the group consisting of hydroxy, C₁ -C₄ alkoxy, Ht,--O--Ht, --NR² --CO--N(R²)(R²) and --CO--N(R²)(R²); and --R¹ --C₂ -C₆alkenyl, which is optionally substituted with one to two groupsindependently selected from the group consisting of hydroxy, C₁ -C₄alkoxy, Ht, --O--Ht, --NR² --CO--N(R²)(R²) and --CO--N(R²)(R²);each R¹is independently selected from the group consisting of --C(O)--, S(O)₂--, --C(O)--C(O)--, --O--C(O)--, --O--S(O)₂, --NR² --S(O)₂ --, --NR²--C(O)-- and --NR² --C(O)--C(O)--; each Ht is independently selectedfrom the group consisting of C₃ -C₇ cycloalkyl; C₅ -C₇ cycloalkenyl; C₆-C₁₀ aryl; and 5-7 membered saturated or unsaturated heterocycle,containing one or more heteroatoms selected from N and O, with theproviso that said heterocycle may not be a pyridyl group and whereinsaid heterocycle is optionally benzofused; and wherein any member ofsaid Ht is optionally substituted with one to two substituentsindependently selected from the group consisting of oxo, --OR², --R²,--N(R²)(R²), --R² --OH, --CN, --CO₂ R², --C(O)--N(R²)(R²), --S(O)₂--N(R²)(R²), --N(R²)--C(O)--R₂, --C(O)--R², --S(O)_(n) --R², --OCF₃,--S(O)_(n) --R⁷, methylenedioxy, --N(R²)--S(O)₂ (R²), halo, --CF₃,--NO₂, R⁷ and --O--R⁷ ; each R² is independently selected from the groupconsisting of H and C₁ -C₃ alkyl optionally substituted with R⁷ ; B,when present, is --N(R²)--C(R³)(R³)--C(O)--; x is 0 or 1; each R³ isindependently selected from the group consisting of H, Ht, C₁ -C₆ alkyl,C₂ -C₆ alkenyl, C₃ -C₆ cycloalkyl and C₅ -C₆ cycloalkenyl, wherein anymember of said R³, except H, is optionally substituted with one to twosubstituents independently selected from the group consisting of --OR²,--C(O)--NH--R², --S(O)_(n) --N(R²)(R²), Het, --CN, --SR², --CO₂ R², andNR² --C(O)--R² ; each n is independently 1 or 2; D and D' areindependently selected from the group consisting of R⁷ ; C₁ -C₄ alkylsubstituted with C₃ -C₆ cycloalkyl, --O--R⁷ or R⁷, and optionallysubstituted with one additional substituent selected from C₃ -C₆cycloalkyl, --O--R⁷, R⁷, OR² or --R³ ; C₂ -C₄ alkenyl substituted withC₃ -C₆ cycloalkyl, --O--R⁷ or R⁷, and optionally substituted with oneadditional substituent selected from C₃ -C₆ cycloalkyl, --O--R⁷, R⁷, OR²or --R³ ; C₃ -C₆ cycloalkyl, which is optionally substituted with orfused with R⁷ ; and C₅ -C₆ cycloalkenyl, which is optionally substitutedwith or fused with R⁷ ; each R⁷ is independently selected from the groupconsisting of phenyl and 3-6 membered carbocyclic ring, wherein saidcarbocyclic ring may be saturated or unsaturated and wherein R⁷ isoptionally substituted with one to two groups independently selectedfrom the group consisting of oxo, --OR², --R², --N(R²)(R²),--N(R²)--C(O)--R², --R² --OH, --CN, --CO₂ R², --C(O)--N(R²)(R²), haloand --CF₃ ; E is a 5-membered heterocyclic ring containing one S andoptionally containing N as an additional heteroatom, wherein saidheterocyclic ring is optionally substituted with one to two groupsindependently selected from the group consisting of --CH₃, R⁴ and Ht;and each R⁴ is independently selected from the group consisting of--OR², --C(O)--NHR², --S(O)₂ --NHR², halo, --NR² --C(O)--R² and --CN. 2.The compound according to claim 1, wherein said compound has thestructure of formula XXII: ##STR655## wherein A, D' and E are defined asin claim
 1. 3. The compound according to claim 1, wherein said compoundhas the structure of formula XXIII: ##STR656## wherein x, Ht, R³, D' andE are defined as in claim
 1. 4. The compound according to claim 1,wherein:A is selected from the group consisting of H; --R¹ --Ht; --R¹--C₁ -C₆ alkyl, which is optionally substituted with one to two groupsindependently selected from the group consisting of hydroxy, C₁ -C₄alkoxy, Ht and --O--Ht; and --R¹ --C₂ -C₆ alkenyl, which is optionallysubstituted with one to two groups independently selected from the groupconsisting of hydroxy, C₁ -C₄ alkoxy, Ht and --O--Ht; each R¹ isindependently selected from the group consisting of --C(O)--, --S(O)₂--, --C(O)--C(O)--, --O--CO--, --O--S(O)₂ -- and --NR² --S(O)₂ --; eachHt is independently selected from the group consisting of C₃ -C₇cycloalkyl; C₅ -C₇ cycloalkenyl; C₆ -C₁₀ aryl; and 5-7 memberedsaturated or unsaturated heterocycle, containing one or more heteroatomsselected from N and O, with the proviso that said heterocycle may not bea pyridyl group and wherein said heterocycle is optionally benzofused;and wherein any member of said Ht is optionally substituted with one totwo substituents independently selected from the group consisting ofoxo, --OR², --R², --N(R²)₂, --R² --OH, --CN, --CO₂ R², --C(O)--N(R²)₂and --S(O)₂ --N(R²)₂ ; B, when presents is --NH--CH(R³)--C(O)--; x is 0or 1; each R³ is independently selected from the group consisting of Ht,C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₃ -C₆ cycloalkyl and C₅ -C₆ cycloalkenyl,wherein any member of said R³ is optionally substituted with one to twosubstituents independently selected from the group consisting of --OR²,--C(O)--NH--R², --S(O)_(n) --N(R²)₂, Ht and --CN; n is 1 or 2; and D andD' are independently selected from the group consisting of R⁷ ; C₁ -C₄alkyl substituted with C₃ -C₆ cycloalkyl, --O--R⁷ or R⁷ ; C₂ -C₄ alkenylsubstituted with C₃ -C₆ cycloalkyl, --O--R⁷ or R⁷, and optionallysubstituted with one additional substituent selected from C₃ -C₆cycloalkyl, --O--R⁷, R⁷, OR² or --R³ ; C₃ -C₆ cycloalkyl, which isoptionally substituted with or fused with R⁷ ; and C₅ -C₆ cycloalkenyl,which is optionally substituted with or fused with R⁷ ; with the provisothat when D is attached to N, D may not be methyl or C₂ alkenyl.
 5. Thecompound according to claim 2 or 3, wherein:A is R¹ --Ht; and D' isselected from the group consisting of C₁ -C₃ alkyl and C₃ alkenyl,wherein said alkyl or alkenyl is substituted with one to two groupsindependently selected from the group consisting of C₃ -C₆ cycloalkyl,--O--R⁷ and R⁷, and optionally substituted with one additional --OR². 6.The compound according to claim 3, wherein:R³ is selected from the groupconsisting of C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₅ -C₆ cycloalkyl, C₅ -C₆cycloalkenyl and Ht, wherein Ht is a 5-6 membered saturated orunsaturated heterocycle, and wherein any member of said R³ is optionallysubstituted with one to two substituents independently selected from thegroup consisting of --OR², --C(O)--NH--R², --S(O)_(n) N(R²)(R²)₂, Ht,--CN, --SR², --C(O)₂ R², and NR² --C(O)--R² ; and D' is selected fromthe group consisting of C₁ -C₃ alkyl and C₃ alkenyl, wherein said alkylor alkenyl is substituted with one to two groups independently selectedfrom the group consisting of C₃ -C₆ cycloalkyl, --O--R⁷ and R⁷, andoptionally substituted with one additional --OR².
 7. A compound selectedfrom the group consisting of:4-Fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 35); 3,4-Dichloro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 37); N-(4-(((2syn,3S)-2-Hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)acetamide(compound 44);
 2. 4-Dimethyl-thiazole-5-sulfonicacid-(1,1-dimethyl-ethoxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-isobutyl-amide (compound 46);N-(4-(((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 48); 4-Fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamideand 4-Fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compounds 52); Benzo(1,2,5)oxadiazole-5-sulfonic acid ((2syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-isobutylamide(compound 66); N-(4-(((2syn,3S)-2-Hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-sulfamoyl-phenyl)-acetamideand N-(4-(((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compounds 86); N-(2-Fluoro-5-(((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 88); N-(3-(((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 91); 4-Fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 93);N-(4-(((syn)-2-Hydroxy-(S)-4-phenyl-3-((tetrahydrofuran-(R)-3-yl)-oxycarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 94); 4-Fluoro-N-(2syn,3S)-2-hydroxy-4-phenyl-3-((tetrahydro-furan-(R)-3-ylmethoxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamideand 4-Fluoro-N-(2syn,3S)-2-hydroxy-4-phenyl-3-((tetrahydro-furan-(S)-3-ylmethoxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compounds 97); 4-Fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 98); 4-Chloro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-benzenesulfonamide(compound 99); N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-4-methoxy-benzenesulfonamide(compound 100);4-Fluoro-N-(2-(syn)-hydroxy-3-((2-oxazolidon-(S)-4-yl)-methoxycarbonylamino)-4-(S)-phenyl-butyl)-N-isobutyl-benzenesulfonamide(compound 109); Benzene-1,3-disulfonic acid 1-amide 3-((2syn,3S)-2-hydroxy-4-phenyl-3-(3-(S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide(compound 112); Furan-3-sulfonic acid (2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide(compound 113); N-((3-Allyloxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-N-cyclopentylmethyl-4-fluoro-benzenesulfonamide(compound 114); N-Cyclopentylmethyl-N-((3-ethoxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-4-fluoro-benzenesulfonamide (compound115); 4-Chloro-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 116); 4-Chloro-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3yl-methoxycarbonyl)-butyl)-benzenesulfonamide(compound 118); N-(4-(Cyclopentylmethyl-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-sulfamoyl)-phenyl)-acetamide(compound 125); 3-Chloro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 138);4-Chloro-N-cyclopentylmethyl-N-(2-(syn)-hydroxy-3-((2-oxazolidon-4-(S)-yl-methyl)-oxycarbonylamino)-4-phenyl-butyl)-benzenesulfonamide(compound 139); N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-methoxy-benzenesulfonamide(compound 140); N-((3-allyloxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-N-cyclopentylmethyl-4-methoxy-benzenesulfonamide(compound 141); N-Cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(3-pyridin-3-yl-methoxycarbonylamino)-butyl-4-methoxy-benzenesulfonamide(compound 142); Pyridine-3-sulfonic acid ((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide,trifluoroacetic acid salt (compound 144);5-Isoxazol-3-yl-thiophene-2-sulfonic acid ((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide(compound 145); N-(4-((3-(Allyloxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-cyclopentylmethylsulfamoyl)-phenyl)-acetamide(compound 146); N-(4-(Cyclopentylmethyl-((2syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-sulfamoyl)-phenyl)-acetamide(compound 147); N-Cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 148); Pyridine-3-sulfonic acid cyclopentylmethyl-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-amide(compound 149); Piperidine-1-sulfonic acid ((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide(compound 150);N-4-((2-(syn)-Hydroxy-3-((2-methoxymethyl-allyloxycarbonylamino)-4-(S)-phenyl-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 155); 1-Acetyl-2,3-dihydro-1H-indole-6-sulfonic acid((allyloxycarbonylamino)-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-cyclopentylmethyl-amide (compound156); 1-Acetyl-2,3-dihydro-1H-indole-6-sulfonic acidcyclopentylmethyl-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-amide(compound 157); N-Cyclohexylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-methoxy-benzenesulfonamide(compound 158); N-Cyclohexylmethyl-4-fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 159); N-(4-(Cyclohexylmethyl)-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-sulfamoyl-phenyl)-acetamide(compound 160); N-((2syn,3S)-2-Hydroxy-4-phenyl-3-(pyridin-4-yl-methoxycarbonylamino)-butyl)-N-isobutyl-4-methoxy-benzenesulfonamide(compound 163); N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((syn)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-4-methyl-benzenesulfonamide(compound 165); N-cyclopentylmethyl-4-hydroxy-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-benzenesulfonamide(compound 166); N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-4-nitro-benzenesulfonamide(compound 167); 4-Amino-N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 168); N-Cyclopentylmethyl-4-hydroxy-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 169); N-Cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-nitro-benezensulfonamide(compound 170); 4-Amino-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 171); 2,4-Diamino-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 173); 4-Hydroxy-N-(2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 175); N-Cyclopentylmethyl-4-fluoro-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 182); 3,4-Dichloro-N-cyclopentylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-benzenesulfonamide(compound 183); Benzyloxycarbonyl-(L)-isoleucine-N-(5-((3-amino-(2syn,3S)-2-hydroxy-4-phenyl-butyl)-isobutyl-sulfamoyl)-2-fluoro-phenyl)-acetamide(compound 187);N-((4S,2S)-4-Cyclohexyl-2-hydroxy-3-((syn)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-cyclopentylmethyl-4-methoxy-benzenesulfonamide(compound 195); N-(4-(((2syn,3S)-3-(t-Butyldicarbonylamino)-2-hydroxy-4-phenyl-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 1001); N-(4-(((2syn,3S)-2-Hydroxy-4-phenyl-3-((R)-2-pyrrolidinone-4-ylmethylcarbonylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide(compound 1002); Pyridine-3-sulfonic acid ((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide(compound 1003); 3-Amino-4-hydroxy-N-(2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 1004); N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-methoxy-N-methylbenzenesulfonamide(compound 1005); N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-methoxy-N-(2-methylpropen-2-yl)benzenesulfonamide(compound 1006); N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-tetrahydrofuran-2-ylmethyl-4-methoxy-benzenesulfonamide(compound 1007); N-Furan-2-ylmethyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-methoxy-benzenesulfonamide(compound 1008); N-2,2-Dimethyl-3-hydroxypropyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-methoxy-benzenesulfonamide(compound 1009); N-2-hydroxy-2-methylpropyl-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-4-methoxy-benzenesulfonamide(compound 1010); N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-piperidin-4-yl-4-methoxybenzenesulfonamide (compound 1011); N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-3-acetylpiperidin-4-yl-4-methoxybenzenesulfonamide (compound 1012); N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-piperidin-4-ylmethyl-4-methoxybenzenesulfonamide (compound 1013); N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-piperidin-4-ylethyl-4-methoxybenzenesulfonamide (compound 1014); and
 3. 4-Diamino-N-((2syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide(compound 1015).
 8. The compound according to claim 1, wherein saidcompound has a molecular weight less than or equal to about 700 g/mol.9. A compound according to claim 8, wherein said compound has amolecular weight less than or equal to about 600 g/mol.
 10. Apharmaceutical composition comprising a pharmaceutically effectiveamount of a compound according to any one of claims 1-3 and apharmaceutically acceptable carrier, adjuvant or vehicle.
 11. A methodfor treating or preventing a viral disease in a mammal caused by a virusthat requires an aspartyl protease for an obligatory life cycle event,said method comprising the step of administering to said mammal acompound according to any one of claims 1-3.
 12. The method according toclaim 11, wherein said virus is HIV-1, HIV-2, or HTLV.
 13. A method forpreventing HIV infection in a mammal comprising the step ofadministering to said mammal a pharmaceutically effective amount of apharmaceutical composition according to claim
 10. 14. A method fortreating HIV infection in a mammal comprising the step of administeringto said mammal a pharmaceutically effective amount of a pharmaceuticalcomposition according to claim
 10. 15. The method according to claim 13or 14, wherein said step of administering comprises oral administrationor administration by injection.
 16. The compound according to claim 1,wherein:R¹ is --O--C(O)--; each D' is independently selected from thegroup consisting of C₁ -C₄ alkyl substituted with one to two groupsselected from C₃ -C₆ cycloalkyl, --O--R⁷ or R⁷, and optionallysubstituted with one additional --OR² or --R³ ; C₂ -C₄ alkenylsubstituted with one to two groups selected from C₃ -C₆ cycloalkyl,--O--R⁷ or R⁷, and optionally substituted with an additional --O² or--R³ ; C₃ -C₆ cycloalkyl, which is optionally substituted with or fusedwith R⁷ ; and C₅ -C₆ cycloalkenyl, which is optionally substituted withor fused with R⁷ ; and E is a 5-membered saturated or unsaturatedheterocycle, containing one S and optionally containing N as anadditional heteroatom, wherein said heterocycle may optionally bebenzofused; and wherein any member of said heterocycle may be optionallysubstituted with one to two substituents independently selected from thegroup consisting of oxo, --OR², --R², --N(R²)(R²), --R² --OH, ---CN,--CO₂ R, --C(O)--N(R²)(R²), --S(O)₂ --N(R²)(R²), --N(R²)--C(O)--R₂,--C(O)--R², --S(O)_(n) --R², --OCF₃, --S(O)_(n) --R⁷, methylenedioxy,--N(R²)--S(O)₂ (R²), halo, --CF₃, --NO₂, R⁷ and --O--R⁷.
 17. Thecompound according to claim 16, wherein said compound is: ##STR657##5-Isoxazol-3-yl-thiophene-2-sulfonic acid ((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-isobutyl-amide(compound 145).
 18. The pharmaceutical composition according to claim10, wherein the viral infection is HIV 1 or HIV 2.